The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a solvate of these. A compound having Nrf2 activation ability is provided by the present invention.
##STR00001##
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5. 5-(indazol-1-yl)-1-oxo-1,2-thiazol-3-ol, or a pharmaceutically acceptable salt, a solvate or an optical isomer thereof.
6. 5-(5-bromoindazol-1-yl)-1-oxo-1,2-thiazol-3-ol, or a pharmaceutically acceptable salt, a solvate or an optical isomer thereof.
7. 5- [5-(2-methoxypyridin-4-yl) indazol-1-yl]-1-oxo-1,2-thiazol-3-ol, or a pharmaceutically acceptable salt, a solvate or an optical isomer thereof.
8. 5-[5-(6-cyclopropylpyridin-3-yl) indazol-1-yl]-1-oxo-1,2-thiazol-3-ol, or a pharmaceutically acceptable salt, a solvate or an optical isomer thereof.
9. 5-[5-(4-methyl 2, 3-dihydropyrido[3,2-b][1, 4]oxazin-7-yl)indazol-1-yl]-1-oxo-1,2-thiazol-3-ol, or a pharmaceutically acceptable salt, a solvate or an optical isomer thereof.
4. A compound which is selected from:
5-(indazol-1-yl)-1-oxo-1,2-thiazol-3-ol,
5-(5-bromoindazol-1-yl)-1-oxo-1,2-thiazol-3-ol,
5-[5-(2-methoxypyridin-4-yl) indazol-1-yl]-1-oxo-1,2-thiazol-3-ol,
5-[5-(6-cyclopropylpyridin-3-yl) indazol-1-yl]-1-oxo-1,2-thiazol-3-ol,
5-[5-(4-methyl-2, 3-dihydropyrido[3,2-b][1, 4]oxazin-7-yl)indazol-1-yl]-1-oxo-1,2-thiazol-3-ol,
or a pharmaceutically acceptable salt thereof or a solvate of these, or an optical isomer of these.
3. A compound, a pharmaceutically acceptable salt, a solvate or an optical isomer thereof selected from the following structures:
##STR00106##
##STR00107##
##STR00108##
##STR00109##
##STR00110##
##STR00111##
##STR00112##
##STR00113##
##STR00114##
##STR00115##
##STR00116##
##STR00117##
##STR00118##
##STR00119##
##STR00120##
##STR00121##
##STR00122##
##STR00123##
##STR00124##
##STR00125##
##STR00126##
##STR00127##
##STR00128##
##STR00129##
##STR00130##
##STR00131##
##STR00132##
##STR00133##
##STR00134##
##STR00135##
##STR00136##
##STR00137##
##STR00138##
##STR00139##
##STR00140##
##STR00141##
##STR00142##
##STR00143##
##STR00144##
##STR00145##
##STR00146##
##STR00147##
##STR00148##
##STR00149##
##STR00150##
##STR00151##
##STR00152##
##STR00153##
##STR00154##
##STR00155##
##STR00156##
##STR00157##
##STR00158##
##STR00159##
##STR00160##
##STR00161##
##STR00162##
##STR00163##
##STR00164##
##STR00165##
##STR00166##
##STR00167##
##STR00168##
##STR00169##
##STR00170##
##STR00171##
##STR00172##
##STR00173##
##STR00174##
##STR00175##
##STR00176##
1. A compound represented by formula (I) below, or a pharmaceutically acceptable salt thereof or a solvate of these:
##STR00104##
wherein the formula, R1 represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group, a cyano group, a c3-8 cycloalkyl group, a c3-8 cycloalkenyl group, a c6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group and a c6-14 arylcarbonyl group,
R2 represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group, a cyano group, a c3-8 cycloalkyl group, a c3-8 cycloalkenyl group, a c6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a c7-20 aralkyl group, a heteroaryl c1-6 alkyl group, a c6-14 aryloxy c1-6 alkyl group and a heteroaryloxy c1-6 alkyl group,
R3 represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group and a cyano group,
R4 represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group and a cyano group,
each of R1 R2 and R3 is optionally substituted with 1 to 5 of R5,
each R5 independently represents a group arbitrarily selected from a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group, a cyano group, a c1-6 alkoxycarbonyl group, a —NRbRc group (in which each of Rb and Rc independently represents a hydrogen atom, a c1-6 alkyl group or a non-aromatic heterocyclic group), a mono/di-c1-6 alkylamino c1-6 alkyl group, a c3-8 cycloalkyl group, a c3-8 cycloalkenyl group, a c6-14 aryl group, non-aromatic heterocyclic group, heteroaryl group, a c3-8 cycloalkyl c1-6 alkyl group, a c7-20 aralkyl group, non-aromatic heterocyclic c1-6 alkyl group, a heteroaryl c1-6 alkyl group, a c6-14 aryloxy group, heteroaryloxy group, a c7-20 aralkyloxy group and a heteroaryl c1-6 alkyloxy group,
each of the c3-8 cycloalkyl group, c3-8 cycloalkenyl group, c6-14 aryl group, non-aromatic heterocyclic group, heteroaryl group, c3-8 cycloalkyl c1-6 alkyl group, c7-20 aralkyl group, non-aromatic heterocyclic c1-6 alkyl group, heteroaryl c1-6 alkyl group,c6-14 aryloxy group, heteroaryloxy group, c7-20 aralkyloxy group or heteroaryl c1-6 alkyloxy group in R5 is optionally substituted with 1 to 5 of a group arbitrarily selected from a halogen atom, a c1-6 alkyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a cyano group, a c1-6 alkoxycarbonyl group, a c3-8 cycloalkyl group, a c3-8 cycloalkenyl group, a c6-14 aryl group (which is itself optionally substituted with 1 to 5 c1-6 alkyl groups), a non-aromatic heterocyclic group and a heteroaryl group,
R2 may bind with R1 or R3 to form a fused ring group together with part of a pyrazole ring, and this fused ring group is a 5- to 10-member heterocyclic group or c6-10 aryl group optionally substituted with 1 to 5 of R6,
each R6 independently represents a group arbitrarily selected from a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group, a cyano group, a c1-6 alkoxycarbonyl group, a c3-8 cycloalkyl group, a c3-8 cycloalkenyl group, a c6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a c3-8 cycloalkyl c1-6 alkyl group, a c7-20 aralkyl group, a heteroaryl c1-6 alkyl group, aC6-14 aryloxy group, a heteroaryloxy group, a c7-20 aralkyloxy group and a heteroaryl c1-6 alkyloxy group,
each R6 is optionally substituted with 1 to 5 of R7,
each R7 independently represents a group arbitrarily selected from a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group, a c1-6 alkoxy c1-6 alkyl group, a cyano group, a c1-6 alkoxycarbonyl group, a —CONRdRe group (in which each of Rd and Re independently represents a hydrogen atom, a c1-6 alkyl group, a c3-8 cycloalkyl group or a c6-14 aryl group), a mono/di-c2-7 alkanoylamino group, an amino group, a mono/di-c1-6 alkylamino group, a mono/di-c1-6 alkylamino c1-6 alkyl group, a c3-8 cycloalkyl group, a c3-8 cycloalkenyl group, a c6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a c3-8 cycloalkyl c1-6 alkyl group, a c7-20 aralkyl group, a non-aromatic heterocyclic c1-6 alkyl group, a heteroaryl c1-6 alkyl group, a c6-14 aryloxy group, heteroaryloxy group, a c3-8 cycloalkylcarbonyl group, a group, a c6-14 arylcarbonyl group and a non-aromatic heterocyclic carbonyl group, and
each of the c3-8 cycloalkyl group, c3-8 cycloalkenyl group, c6-14 aryl group, non-aromatic heterocyclic group, heteroaryl group, c3-8 cycloalkyl c1-6 alkyl group, c7-20 aralkyl group, non-aromatic heterocyclic c1-6 alkyl group, heteroaryl c1-6 alkyl group, c6-14 aryloxy group, heteroaryloxy group, c3-8 cycloalkylcarbonyl group, c6-14 arylcarbonyl group or non-aromatic heterocyclic carbonyl group of R7 is optionally substituted with 1 to 5 of a halogen atom, a c1-6 alkyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group or a c1-6 alkoxy c1-6 alkyl group.
2. The compound represented by formula (I)-1 below or a pharmaceutically acceptable salt thereof or a solvate of these according to
##STR00105##
wherein the formula, R1a a represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group, a cyano group, a c3-8 cycloalkyl group and a c6-14 arylcarbonyl group,
each R1a is optionally substituted with 1 to 5 halogen atoms,
each R6a independently represents a group arbitrarily selected from a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group, a cyano group, a c3-8 cycloalkyl group, a c3-8 cycloalkenyl group, a c6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a c6-14 aryloxy group, a heteroaryloxy group, a c7-20 aralkyloxy group and a heteroaryl c1-6 alkyloxy group,
each R6a is optionally substituted with 1 to 5 of R7a,
each R7a independently represents a group arbitrarily selected from a halogen atom, a c1-6 alkyl group, a c2-6 alkenyl group, a c2-6 alkynyl group, a halogenated c1-6 alkyl group, a c1-6 alkoxy group, a c2-6 alkenyloxy group, a c2-6 alkynyloxy group, a c1-6 alkoxy c1-6 alkyl group, a cyano group, a c1-6 alkoxycarbonyl group, a —CONRdRe group (in which each of Rd and Re independently represents a hydrogen atom, a c1-6 alkyl group, a c3-8 cycloalkyl group or a c6-14 aryl group), a mono/di-c2-7 alkanoylamino group, an amino group, a mono/di-c1-6 alkylamino group, a c3-8 cycloalkyl group, a c6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a c3-8 cycloalkyl c1-6 alkyl group, a c7-20 aralkyl group, a non-aromatic heterocyclic c1-6 alkyl group, a heteroaryl c1-6 alkyl group, a c6-14 aryloxy group, a heteroaryloxy group, a c3-8 cycloalkylcarbonyl group, a c6-14 arylcarbonyl group and a non-aromatic heterocyclic carbonyl group, and
the c3-8 cycloalkyl group, non-aromatic heterocyclic group, c3-8 cycloalkyl c1-6 alkyl group, non-aromatic heterocyclic c1-6 alkyl group, c6-14 aryloxy group, c3-8 cycloalkylcarbonyl group, c6-14 arylcarbonyl group or non-aromatic heterocyclic carbonyl group in each R7a is optionally substituted with 1 to 5 halogen atoms, c1-6 alkyl groups, halogenated c1-6 alkyl groups, c1-6 alkoxy groups or c1-6 alkoxy c1-6 alkyl groups, and n represents 0, 1 or 2.
10. A pharmaceutical composition containing as an active ingredient at least one of the compound or a pharmaceutically acceptable salt, or a solvate thereof according to
11. A pharmaceutical composition containing as an active ingredient at least one of the compound or a pharmaceutically acceptable salt or a solvate thereof according to
12. A pharmaceutical composition containing as an active ingredient at least one of the compound or a pharmaceutically acceptable salt or a solvate thereof according to
13. A pharmaceutical composition containing as an active ingredient at least one of the compound or a pharmaceutically acceptable salt or a solvate thereof according to
14. A pharmaceutical composition containing as an active ingredient at least the compound, a pharmaceutically acceptable salt or solvate thereof according to
15. A pharmaceutical composition containing as an active ingredient at least the compound, a pharmaceutically acceptable salt or solvate thereof according to
16. A pharmaceutical composition containing as an active ingredient at least the compound, a pharmaceutically acceptable salt or solvate thereof according to
17. A pharmaceutical composition containing as an active ingredient at least the compound, a pharmaceutically acceptable salt or solvate thereof according to
18. A pharmaceutical composition containing as an active ingredient at least the compound, a pharmaceutically acceptable salt or solvate thereof according to
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The present invention relates to a compound having Nrf2 activation ability, and particularly to a compound having an isothiazole structure represented by Formula (I) below or a pharmaceutically acceptable salt thereof or a solvate of these, and to a pharmacological composition having these as active ingredients. The present invention also relates to a preventative and/or treatment agent for diseases associated with Nrf2, such as multiple sclerosis, psoriasis and the like.
Nrf2 (nuclear factor erythroid 2-related factor 2) is a protein in the cap'n'collar transcription factor family that induces cytoprotective genes and plays an important role in protecting against oxidative stress. Under non-stress conditions, Nrf2 is negatively regulated by ubiquitination and proteasomal degradation triggered by Keap1 (Kelch-like ECH-associated protein 1). When Keap1 is exposed to oxidative stimulation and electrophilic stimulation, Nrf2 avoids proteasomal degradation. The Nrf2 then moves to the nucleus, where it forms heterodimers with small Maf proteins and binds to antioxidant response elements (AREs) in antioxidative genes and detoxification genes and induces expression of these genes. This stress response gene regulatory system is called the “Keap1-Nrf2 system”.
In addition to its antioxidative function and detoxification function, the Keap1-Nrf2 system also appears to be involved in metabolic homeostasis, and compounds that activate this system have been considered as potential treatment agents for various diseases (NPL 1, NPL 2). Specific diseases associated with Nrf2 include autoimmune diseases (multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, etc.), central nervous system diseases (Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, etc.), malignant tumors (melanoma, lung cancer, medulloblastoma, neuroblastoma, etc.), respiratory diseases (chronic occlusive pulmonary disease, etc.), eye diseases (ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, etc.), skin diseases (dermatitis, radiation skin disorders, epidermolysis bullosa, etc.), kidney diseases (diabetic nephropathy, etc.), circulatory diseases (pulmonary arterial hypertension, etc.), liver diseases (hepatitis, liver cirrhosis, etc.), traumatic brain injury, aging, diabetes, obesity and the like.
Compounds having Nrf2 activation ability include sulforaphane, lithospermic acid B (LAB), oltipraz, bardoxolone methyl (CDDO-Me), curcumin and dimethyl fumarate (BG-12), and along with their Nrf2 activating effects, application of these to various diseases has been suggested (NPL 2 and NPL 3).
A compound having a purine ring and a tetrahydrothiophene structure is disclosed in WO 2011/156889 (PTL 1) as a compound having Nrf2 activation ability. However, its basic framework is different from that of a compound having an isothiazole ring structure, and the compound of the present invention is neither disclosed nor suggested.
In the field of drug development, strict criteria must be met not only in terms of the intended pharmacological activity, but also in the areas of absorption, distribution, metabolism, excretion and the like. For example, various tests are required for drug interactions, desensitization and resistance, gastrointestinal absorption upon oral administration, transfer rate into the small intestine, absorption rate and first pass effect, organ barriers, protein binding, induction and inhibition of drug metabolizing enzymes, excretory route and clearance, application methods (application site, methods, object) and the like, and it is rare that all of these criteria are satisfied. However, these problems are common to all medicines.
There have been multiple reports of compounds having Nrf2 activation ability, but the general issues mentioned above with respect to drug development are always present. More particularly, there are problems of utility and safety, such as for example poor solubility, difficulty of systemic exposure through oral administration due to poor metabolic stability, poor pharmacokinetics such as absorbability and persistence, risk of arrhythmia due to inhibition of the hERG (human ether-a-go-go related gene) channel, induction or inhibition of drug metabolizing enzymes (such as cytochrome P450), and strong protein binding. Drugs need to be discovered that are highly effective while avoiding these problems as much as possible.
The inventors discovered as a result of exhaustive research aimed at finding a highly safe and/or highly effective Nrf2 activator that a compound having an isothiazole structure represented by Formula (I) or a pharmaceutically acceptable salt thereof or a solvate of these has Nrf2 activation ability. The compound of the present invention has Nrf2 activation ability, and preferably has an improving effect on diseases associated with Nrf2, especially multiple sclerosis, psoriasis and the like.
##STR00002##
The present invention is a compound having an isothiazole structure represented by Formula (I), or a pharmaceutically acceptable salt thereof or a solvate of these, as well as a pharmacological composition containing these as an active ingredient.
The compound of the invention is a compound having Nrf2 activation ability, and preferably having an improving effect on diseases associated with Nrf2, especially multiple sclerosis, psoriasis and the like.
A pharmacological composition containing the compound of the present invention as an active ingredient is preferably one that can be orally administered, and holds promise as a preventative and/or treatment agent for diseases associated with Nrf2, such as multiple sclerosis and psoriasis.
Moreover, preferably the compounds of the present invention are highly useful because they have at least one feature such as good solubility, high metabolic stability, excellent oral absorbability, or a low inhibitory effect on the hERG channel.
The present invention is a compound having an isothiazole structure represented by Formula (I) below as shown in the following embodiments, or a pharmaceutically acceptable salt thereof or a solvate of these, as well as a pharmacological composition containing these as an active ingredient, a medicinal use of these, and an Nrf2 activator.
[Embodiments of the Invention]
The present invention comprises the following Embodiments [1] to [11].
[1] Embodiment 1 of the invention is a compound represented by Formula (I) below, or a pharmceutically acceptable salt thereof or a solvate of these:
##STR00003##
(in the formula, R1 represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group and a C6-14 arylcarbonyl group,
R2 represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a C7-20 aralkyl group, a heteroaryl C1-6 alkyl group, a C6-14 aryloxy C1-6 alkyl group and a heteroaryloxy C1-6 alkyl group,
R3 represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group and a cyano group,
R4 represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group and a cyano group,
each of R1, R2 and R3 is optionally substituted with 1 to 5 of R5,
each R5 independently represents a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a cyano group, a C1-6 alkoxycarbonyl group, a —NRbRc group (in which each of Rb and Rc independently represents a hydrogen atom, a C1-6 alkyl group or a non-aromatic heterocyclic group), a mono/di-C1-6 alkylamino C1-6 alkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group, non-aromatic heterocyclic group, a heteroaryl group, a C3-8 cycloalkyl C1-6 alkyl group, a C7-20 aralkyl group, non-aromatic heterocyclic C1-6 alkyl group, a heteroaryl C1-6 alkyl group, a C6-14 aryloxy group, a heteroaryloxy group, a C7-20 aralkyloxy group and a heteroaryl C1-6 alkyloxy group,
each of the C3-8 cycloalkyl group, C3-8 cycloalkenyl group, C6-14 aryl group, non-aromatic heterocyclic group, heteroaryl group, C3-8 cycloalkyl C1-6 alkyl group, C7-20 aralkyl group, non-aromatic heterocyclic C1-6 alkyl group, heteroaryl C1-6 alkyl group, C6-14 aryloxy group, heteroaryloxy group, C7-20 aralkyloxy group or heteroaryl C1-6 alkyloxy group of each R5 is optionally substituted with 1 to 5 of a group optionally selected from a halogen atom, C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a cyano group, a C1-6 alkoxycarbonyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group (which is itself optionally substituted with 1 to 5 C1-6 alkyl groups), a non-aromatic heterocyclic group and a heteroaryl group,
R2 may bind with R1 or R3 to form a fused ring group together with part of a pyrazole ring, and this fused ring group is a 5- to 10-member heterocyclic group or a C6-10 aryl group optionally substituted with 1 to 5 of R6,
each R6 independently represents a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a cyano group, a C1-6 alkoxycarbonyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a C3-8 cycloalkyl C1-6 alkyl group, a C7-20 aralkyl group, a heteroaryl C1-6 alkyl group, a C6-14 aryloxy group, a heteroaryloxy group, a C7-20 aralkyloxy group and a heteroaryl C1-6 alkyloxy group,
each R6 is optionally substituted with 1 to 5 of R7,
each R7 independently represents a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a C1-6 alkoxy C1-6 alkyl group, a cyano group, a C1-6 alkoxycarbonyl group, a —CONRdRe group (in which each of Rd and Re independently represents a hydrogen atom, a C1-6 alkyl group, C3-8 cycloalkyl group or a C6-14 aryl group), a mono/di-C2-7 alkanoylamino group, an amino group, a mono/di-C1-6 alkylamino group, a mono/di-C1-6 alkylamino C1-6 alkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a C3-8 cycloalkyl C1-6 alkyl group, a C7-20 aralkyl group, a non-aromatic heterocyclic C1-6 alkyl group, a heteroaryl C1-6 alkyl group, a C6-14 aryloxy group, a heteroaryloxy group, a C3-8 cycloalkylcarbonyl group, a C6-14 arylcarbonyl group and a non-aromatic heterocyclic carbonyl group, and
each of the C3-8 cycloalkyl group, C3-8 cycloalkenyl group, C6-14 aryl group, non-aromatic heterocyclic group, heteroaryl group, C3-8 cycloalkyl C1-6 alkyl group, C7-20 aralkyl group, non-aromatic heterocyclic C1-6 alkyl group, heteroaryl C1-6 alkyl group, C6-14 aryloxy group, heteroaryloxy group, C3-8 cycloalkylcarbonyl group, C6-14 arylcarbonyl group or non-aromatic heterocyclic carbonyl group of each R7 is optionally substituted with 1 to 5 of a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group or a C1-6 alkoxy C1-6 alkyl groups).
Each group in Formula (I) of Embodiment [1] above is explained in detail below.
In explanations of the compound of the invention, “C1-6” for example indicates that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, this represents the total number of carbon atoms in a linear, branched or cyclic group. In a group containing a chain group and a cyclic group, it means the “total number of carbon atoms in the chain and the ring”.
In this Description, unless otherwise specified, a “halogen atom” may be for example a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
In this Description, unless otherwise specified, “halogenated” means having 1 to 5 of the aforementioned “halogen atom” as substituents.
In this Description, unless otherwise specified, examples of the “C1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl and the like. Examples of the “C1-4 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Examples of the “C1-2 alkyl group” include methyl and ethyl.
In this Description, unless otherwise specified, a “halogenated C1-6 alkyl group” means a group comprising the “C1-6 alkyl group” optionally substituted with 1 to 5 halogen atoms, and examples include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
In this Description, unless otherwise specified, a “halogenated C1-4 alkyl group” means a group comprising the “C1-4 alkyl group” optionally substituted with 1 to 5 halogen atoms, and examples include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
In this Description, unless otherwise specified, a “halogenated C1-2 alkyl group” means a group comprising the “C1-2 alkyl group” optionally substituted with 1 to 5 halogen atoms, and examples include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl and the like.
In this Description, unless otherwise specified, a “C2-6 alkenyl group” may be a vinyl, allyl, isopropenyl, 1-propene-1-yl, butenyl, pentenyl, isopentenyl or hexenyl group or the like for example.
In this Description, unless otherwise specified, a “C2-6 alkynyl group” may be an ethynyl, 1-propynyl (=1-propyn-1-yl), 2-propynyl (=2-propyn-1-yl), butynyl, pentynyl (=4-pentyn-1-yl), hexynyl (=5-hexyny-1-yl) group or the like for example.
In this Description, unless otherwise specified, a “C3-8 cycloalkyl group” may be a cyclic alkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group or the like for example.
In this Description, unless otherwise specified, a “C3-8 cycloalkenyl group” may be a cyclic alkenyl group such as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group or the like for example.
In this Description, unless otherwise specified, a “C3-6 cycloalkyl group” may be a cyclic alkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group or the like for example.
In this Description, unless otherwise specified, a “C3-6 cycloalkenyl group” may be a cyclic alkenyl group such as a cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group or the like for example.
In this Description, unless otherwise specified, an “aryl group” may be a “monocyclic aryl group”, a “condensed cyclic aryl group (including bicyclic or tricyclic)” or a “partial hydrogenated condensed cyclic aryl group”.
In this Description, unless otherwise specified, a “partially hydrogenated condensed cyclic aryl group” is a monovalent group obtained by removing any hydrogen atom from a partially hydrogenated fused ring in the aforementioned “condensed cyclic aryl group”, and either a hydrogen atom of the aromatic ring portion of the fused ring or a hydrogen atom of the hydrogenated portion may be removed.
In this Description, unless otherwise specified, a “C6-14 aryl group” may be a phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, acenaphthyl, indanyl, indenyl, 1,2-dihydronaphthyl or 1,2,3,4-tetrahydronaphthyl group or the like for example.
In this Description, unless otherwise specified, a “C6-10 aryl group” may be a phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, 1,2-dihydronaphthyl or 1,2,3,4-tetrahydronaphthyl group or the like for example.
In this Description, unless otherwise specified, a “heterocyclic group” is a monovalent group obtained by removing any hydrogen atom from a 3- to 14-member monocyclic or fused ring containing 1 to 5 hetero atoms selected from nitrogen, sulfur and oxygen atoms, and a carbonyl group may also be substituted for a carbon atom in a ring of this heterocyclic group.
In this Description, unless otherwise specified, examples of “heterocyclic groups” include a “heteroaryl group”, a “non-aromatic heterocyclic group” and the like.
In this Description, unless otherwise specified, the aforementioned “heteroaryl group” is a 5- to 14-member heteroaryl group containing 1 to 5 hetero atoms selected from nitrogen, sulfur and oxygen atoms, and a carbonyl group may also be substituted for a carbon atom in a ring of this heteroaryl group.
In this Description, unless otherwise specified, examples of “heteroaryl groups” include a “monocyclic heteroaryl group”, a “condensed cyclic heteroaryl group” and a “partially hydrogenated condensed cyclic heteroaryl group”.
In this Description, unless otherwise specified, the aforementioned “monocyclic heteroaryl group” is preferably one having 5 to 7 ring members, and examples include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiatriazolyl, oxatriazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazyl, tetrazyl, 2-oxo-1H-pyridyl, 2,3′-bipyridinyl, 2,4′-bipyridinyl and the like.
In this Description, unless otherwise specified, the aforementioned “condensed cyclic heteroaryl group” is a monovalent group obtained by removing any arbitrary hydrogen atom from a fused ring formed by condensing a “heterocyclic group” with an “aryl group” or a “heterocyclic group” with a “heteroaryl group”, and the arbitrary hydrogen atom may be removed from either condensed ring.
In this Description, unless otherwise specified, the aforementioned “condensed cyclic heteroaryl group” is preferably one having 8 to 14 ring members, and examples include indolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 2H-indazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, quinoxalinyl, pyrido[2,3-b]pyrazinyl, pyrido[2,3-b][1,4]oxazinyl, furo[3,2-b]pyridyl, pyrrolo[3,2-b]pyridyl, pyrazolo[1,5-a]pyrimidinyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[4,3-b]pyridyl, pyrazolo[3,4-c]quinolyl, 1-oxo-2H-isoquinolyl, 2-oxobenzimidazolyl, 2-oxoindolyl, 2-oxo-1,3-benzooxazolyl and the like.
In this Description, unless otherwise specified, a “partially hydrogenated condensed cyclic heteroaryl group” is a monovalent group obtained by removing any arbitrary hydrogen atom from a partially hydrogenated condensed ring in a fused ring formed by condensing a “heterocyclic group” with an “aryl group” or a “heterocyclic group” with a “heteroaryl group”. The arbitrary hydrogen atom may be removed either from any ring part (the “heterocyclic group”, “aryl group” or “heteroaryl group”) in the fused ring, or from a hydrogenated ring part, and for example in the case of tetrahydroquinolyl having partially hydrogenated quinoline, examples include 5,6,7,8-tetrahydroquinolyl or 1,2,3,4-tetrahydroquinolyl. Depending on the position from which the arbitrary hydrogen atom is removed, these groups may be substituted with -2-yl,-3-yl,-4-yl,-5-yl,-6-yl,-7-yl,-8-yl or the like in the case of 5,6,7,8-tetrahydroquinolyl, or with -1-yl,-2-yl,-3-yl,-4-yl,-5-yl,-6-yl,-7-yl,-8-yl or the like in the case of 1,2,3,4-tetrahydroquinolyl for example.
In this Description, unless otherwise specified, the “partially hydrogenated condensed cyclic heteroaryl group” is preferably one with 8 to 14 ring members, and examples include the following:
indolinyl,
2,3-dihydro-1H-pyrido [2,3-b] [1,4] oxazinyl,
2,3-dihydro-1H-pyrrolo [2,3-b] pyridyl,
3,4-dihydro-1H-1,8-naphthyridinyl,
2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepinyl,
6,7,8,9-tetrahydropyrido [3,2-b] [1,4] oxazocinyl,
7,8,9,10-tetrahydro-6H-pyrido [3,2-b] [1,4] oxazocinyl,
2,3-dihydropyrazino [2,3-b] [1,4] oxazinyl,
6a,7,8,9-tetrahydro-6H-pyrido [3,2-b] pyrrolo [1,2-d] [1,4] oxazinyl,
6,7-dihydro-5H-pyrimido [4,5-b] [1,4] oxazinyl,
3,4-dihydro-2H-pyrido [4,3-b] [1,4] oxazinyl,
3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazinyl,
3,4-dihydro-2H-pyrazino [2,3-b] [1,4] oxazinyl,
2,3-dihydro-[1, 4] dioxino [2,3-b] pyridyl,
2,3-dihydro-1,4-benzodioxinyl,
2,3-dihydrobenzo [b] [1,4] dioxinyl,
3,4-dihydro-2H-benzo [b] [1,4] oxazinyl,
2,3-dihydro-1H-benzo [d] imidazolyl,
2,3-dihydrobenzo [d] oxazolyl,
4,6-dihydropyrrolo [3,4-c] pyrazolyl,
6,7-dihydro-4H-pyrazolo [4,3-c] pyridyl,
4,6,7,8-tetrahydropyrazolo [4,3-c] azepinyl,
4,5,7,8-tetrahydropyrazolo [3,4-d] azepinyl,
2-oxo-1H-pyrido [2,3-b] [1,4] oxazinyl,
2-oxo-1H-3,4-dihydro-1,8-naphthyridinyl,
3-oxo-4H-pyrido [3,2-b] [1,4] oxazinyl,
3-oxo-4H-pyrazino [2,3-b] [1,4] oxazinyl, and
6-oxo-5H-pyrimido [4,5-b] [1,4] oxazinyl.
In this Description, unless otherwise specified, a “non-aromatic heterocyclic group” is a monovalent group obtained by removing any hydrogen atom from a saturated or unsaturated 3- to 14-member non-aromatic heterocyclic ring containing 1 to 5 hetero atoms selected from the oxygen, sulfur and nitrogen atoms, and a carbonyl group may also be substituted for a carbon atom in a ring of this non-aromatic heterocyclic group. In this Description, unless otherwise specified, rings comprising C3-8 cycloalkyls or 3- to 8-member non-aromatic heterocyclic rings spiro bonded to “non-aromatic heterocyclic groups” are also considered “non-aromatic heterocyclic groups”.
In this Description, unless otherwise specified, examples of “non-aromatic heterocyclic groups” include aziridinyl, azetidinyl, oxiranyl, thiiranyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, 3,6-dihydro-2H-pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,6-tetrahydropyridyl, piperazinyl, morpholinyl, thiomorpholinyl, 2-oxa-7-azaspiro[3.4]octanyl, 2-oxopyrrolidinyl and 2-oxopiperidinyl and the like.
In this Description, unless otherwise specified, a “cycloalkylalkyl group” is a group in which the aforementioned “cycloalkyl group” is substituted with the aforementioned “alkyl group”, and examples of “C3-8 cycloalkyl C1-6 alkyl groups” include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl and 2-cyclopropylethyl and the like.
In this Description, unless otherwise specified, an “aralkyl group” is a group in which the aforementioned “aryl group” is substituted with the aforementioned “alkyl group”, and examples of “C7-20 aralkyl groups” include benzyl, phenethyl, diphenylmethyl, trityl, biphenylmethyl, naphthylmethyl, indanylmethyl and 1,2,3,4-tetrahydronaphthalene-1-ylmethyl and the like.
In this Description, unless otherwise specified, an “aralkyl group” is a group in which the “aryl group” is substituted with the “alkyl group”, and examples of “C7-14 aralkyl groups” include benzyl, phenethyl, diphenylmethyl, biphenylmethyl, naphthylmethyl, indanylmethyl and 1,2,3,4-tetrahydronaphthalene-1-ylmethyl and the like.
In this Description, unless otherwise specified, an “aralkyl group” is a group in which the “aryl group” is substituted with the “alkyl group”, and examples of “C7-8 aralkyl groups” include benzyl and phenethyl and the like.
In this Description, unless otherwise specified, a “non-aromatic heterocyclic alkyl group” is a group in which the aforementioned “non-aromatic heterocyclic group” is substituted with the aforementioned “alkyl group”.
In this Description, unless otherwise specified, a “heteroarylalkyl group” is a group in which the aforementioned “heteroaryl group” is substituted with the aforementioned “alkyl group”, such as morpholinemethyl for example.
In this Description, unless otherwise specified, a “C1-6 alkoxy group” is a group in which the “C1-6 alkyl group” is substituted with an oxygen atom.
In this Description, unless otherwise specified, examples of “C1-6 alkoxy groups” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups and the like. Examples of “C1-4 alkoxy groups” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy and the like, while examples of “C1-2 alkoxy groups” include methoxy and ethoxy.
In this Description, unless otherwise specified, a “C1-6 alkoxy C1-6 alkyl group” is a group in which the aforementioned “C1-6 alkoxy group” is substituted with the aforementioned “C1-6 alkyl group”, and examples of “C1-6 alkoxy C1-6 alkyl groups” include methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl and the like.
In this Description, unless otherwise specified, a “C2-6 alkenyloxy group” is a group in which the “C2-6 alkenyl group” is substituted with an oxygen atom, and examples include vinyloxy, allyloxy, isopropenyloxy, butenyloxy, pentenyloxy and hexenyloxy and the like.
In this Description, unless otherwise specified, a “C2-6 alkynyloxy group” is a group in which the “C2-6 alkynyl group” is substituted with an oxygen atom, and examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, butynyloxy, pentynyloxy and hexynyloxy and the like.
In this Description, unless otherwise specified, an “aryloxy group” is a group in which the “aryl group” is substituted with an oxygen atom, such as phenoxy for example.
In this Description, unless otherwise specified, a “heteroaryloxy group” is a group in which the “heteroaryl group” is substituted with an oxygen atom.
In this Description, unless otherwise specified, an “aralkyloxy group” is a group in which the “aralkyl group” is substituted with an oxygen atom.
In this Description, unless otherwise specified, a “heteroarylalkyloxy group” is a group in which the “heteroarylalkyl group” is substituted with an oxygen atom.
In this Description, unless otherwise specified, an “aryloxyalkyl group” is a group in which the “aryloxy group” is substituted with the “alkyl group”.
In this Description, unless otherwise specified, a “heteroaryloxyalkyl group” is a group in which the “heteroaryloxy group” is substituted with the “alkyl group”.
In this Description, unless otherwise specified, a “C2-7 alkanoyl group” means a “C1-6 alkylcarbonyl group” comprising a carbonyl group bound to the “C1-6 alkyl group”, and examples of “C2-7 alkanoyl groups” include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and heptanoyl and the like.
In this Description, unless otherwise specified, a “cycloalkylcarbonyl group” is a group comprising a carbonyl group bound to the “cycloalkyl group”, and examples of “C3-8 cycloalkylcarbonyl groups” include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl and the like.
In this Description, unless otherwise specified, an “arylcarbonyl group” is a group comprising a carbonyl group bound to the “aryl group”, and examples of “C6-14 arylcarbonyl groups” include benzoyl, 1-naphthoyl (1-naphthylcarbonyl), 2-naphthoyl (2-naphthylcarbonyl), indanylcarbonyl, indenylcarbonyl, 1,2,3,4-tetrahydronaphthylcarbonyl and the like.
In this Description, unless otherwise specified, an “arylcarbonyl group” is a group comprising a carbonyl group bound to the “aryl group”, and examples of “C6-10 arylcarbonyl groups” include benzoyl, 1-naphthoyl (1-naphthylcarbonyl), 2-naphthoyl (2-naphthylcarbonyl), indanylcarbonyl, indenylcarbonyl, 1,2,3,4-tetrahydronaphthylcarbonyl and the like.
In this Description, unless otherwise specified, a “non-aromatic heterocyclic carbonyl group” is a group comprising a carbonyl group bound to the “non-aromatic heterocyclic group”, and examples of “non-aromatic heterocyclic carbonyl groups” include aziridinylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofurylcarbonyl, piperidinylcarbonyl, tetrahydropyranylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl and the like.
In this Description, unless otherwise specified, each of Rb and Rc in a “—NRbRc group” independently represents a hydrogen atom, “C1-6 alkyl group” or “non-aromatic heterocyclic group”, and a “—NRbRc group” is a group in which the two hydrogen atoms on the nitrogen atom of an amino group are substituted with Rb and Rc. Examples include dimethylamino, N,N-dimethyltetrahydro-2H-pyranyl-4-amino and the like.
In this Description, unless otherwise specified, a “mono/di-C1-6 alkylamino group” is a group in which one or two hydrogen atoms of the amino group are substituted with the “C1-6 alkyl group”.
In this Description, unless otherwise specified, a “mono/di-C2-7 alkanoylamino group” is a group in which one or two hydrogen atoms of the amino group are substituted with the “C2-7 alkanoyl group”.
In this Description, unless otherwise specified, a “mono/di-C1-6 alkylamino C1-6 alkyl group” is a group in which the “mono/di-C1-6 alkylamino group” is substituted with the “C1-6 alkyl group”.
In this Description, unless otherwise specified, each of Rd and Re in a “—CONRdRe group” independently represents a hydrogen atom, “C1-6 alkyl group”, “C3-8 cycloalkyl group” or “C6-14 aryl group”, and a “—CONRdRe group” is a group in which the two hydrogen atoms on the nitrogen atom of the carbamoyl group are substituted with Rd and Re.
In this Description, unless otherwise specified, a “C1-6 alkoxycarbonyl group” is a group in which the hydrogen atom of a carboxy group is substituted with a “C1-6 alkyl group”, or in other words an “ester group”, and examples include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc) and the like.
In this Description, unless otherwise specified, a “C1-4 alkoxycarbonyl group” is a group in which the hydrogen atom of a carboxyl group is substituted with a “C1-4 alkyl group”, or in other words an “ester group”, and examples include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc) and the like.
R2 may also bind with R1 or R3 to form a fused cyclic group together with part of a pyrazole ring. That is, as shown in the partial structural formula below, R2, R3 and (part of) a pyrazole ring may bind together to form the fused ring F1, or else R2, R1 and (part of) a pyrazole ring may bind together to form the fused ring F2.
##STR00004##
The formed “fused ring F1 or fused ring F2” forms a fused cyclic group together with the adjacent pyrazole ring.
This “fused ring F1 or fused ring F2” is a “C6-10 aryl group” or “5- to 10-member heterocyclic group” optionally substituted with 1 to 5 of R6, and forms a “condensed cyclic heteroaryl group” or “partially hydrogenated condensed cyclic heteroaryl group” together with the adjacent pyrazole ring.
In “R2 may also bind with R1 or R3 to form a fused cyclic group together with part of a pyrazole ring”, the “fused cyclic” or in other words the “fused ring F1 or fused ring F2” is a cyclic group out of the “aryl groups” described above having 6 to 10 carbon members, or a 5- to 10-member cyclic group out of the “heterocyclic groups”.
The fused cyclic group comprising the “fused ring F1 or fused ring F2” and the adjacent pyrazole ring is a fused cyclic group out of the “heterocyclic groups” described above, and specific examples include fused cyclic groups containing pyrazole rings out of the “condensed cyclic heteroaryl groups” and “partially hydrogenated condensed cyclic heteroaryl groups” described above. More specific examples include indazolyl, pyrazolo[3,4-b]pyridyl, pyrazolo [3,4-c]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[4,3-b]pyridyl, pyrazolo[3,4-c]quinolyl, 4,6-dihydropyrrolo[3,4-c]pyrazolyl, 6,7-dihydro-4H-pyrazolo[4,3-c]pyridyl, 4,6,7,8-tetrahydropyrazolo[4,3-c]azepinyl, 4,5,7,8-tetrahydropyrazolo[3,4-d]azepinyl and the like.
In the compound of Formula (I) above, the 3-hydroxy-isothiazolyl group is a group that may become a 3(2H)-isothiazolonyl group through proton tautomerism, and the tautomers that occur are encompassed by Formula (I). The ratios of these structures may vary according to whether the compound represented by Formula (I) is in a solid or a liquid state.
##STR00005##
A description of any specific tautomeric form in any structural formulae in this Description is given not with the intent of limiting the Description to that form, but as a representative of the tautomer set as a whole.
[1-1] In the compound of Formula (I) of Embodiment [1] above, R1 is preferably a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a cyano group, a C3-8 cycloalkyl group, a C6-14 aryl group and a C6-14 arylcarbonyl group, and
more preferably a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a cyano group, a C3-6 cycloalkyl group, a C6-10 aryl group and a C6-10 arylcarbonyl group, or
still more preferably a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-2 alkyl group, a C1-2 alkoxy group, a cyano group, a C3-6 cycloalkyl group, a phenyl and a phenylcarbonyl group, and each of the alkyl group, alkoxy group, cycloalkyl group, aryl group or arylcarbonyl group in R1 above may also be substituted with 1 to 5 of R5.
[1-1-1] Most preferably in the compound of Formula (I) of Embodiment [1] above, R1 is a group arbitrarily selected from a hydrogen atom, a halogen atom and a phenyl group, the phenyl group in R1 above is optionally substituted with 1 to 5 of R5 (with R5 representing a halogen atom), and more specifically R1 represents a hydrogen atom, a chlorine atom or a phenyl group, while R5 represents a bromine atom.
[1-2] In the compound of Formula (I) of Embodiment [1] above, R2 is preferably a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C644 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a C7-20 aralkyl group, a heteroaryl C1-6 alkyl group, a C644 aryloxy C1-6 alkyl group and a heteroaryloxy C1-6 alkyl group, and more preferably a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-4 alkyl group, C24 alkenyl group, a C24 alkynyl group, a halogenated C1-4 alkyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, a C6-10 aryl group, a 5- to 10-member non-aromatic heterocyclic group, a 5- to 10-member heteroaryl group, a C7-14 aralkyl group, a 5- to 10-member heteroaryl C1-4 alkyl group, a C6-10 aryloxy C1-4 alkyl group and a 5- to 10-member heteroaryloxy C1-4 alkyl group, or still more preferably a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-2 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, a halogenated C1-2 alkyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, C640 aryl group, a 5- to 10-member non-aromatic heterocyclic group, a 5- to 10-member heteroaryl group, a C742 aralkyl group, a 5- to 10-member heteroaryl C1-2 alkyl group, a C640 aryloxy C1-2 alkyl group and a 5- to 10-member heteroaryloxy C1-2 alkyl group, and each of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, non-aromatic heterocyclic group, heteroaryl group, aralkyl group, heteroarylalkyl group, aryloxyalkyl group and heteroaryloxyalkyl group in R2 above may be substituted with 1 to 5 of R5.
[1-3] In the compound of Formula (I) of Embodiment [1] above, R3 is preferably a group arbitrarily selected from a hydrogen atom and a C1-6 alkyl group, and more preferably is a group arbitrarily selected from a hydrogen atom and a C1-4 alkyl group, or still more preferably a hydrogen atom or a C1-2 alkyl group, and each alkyl group in R3 above may also be substituted with 1 to 5 of R5.
[1-4] In the compound of Formula (I) of Embodiment [1] above, R4 is preferably a hydrogen atom.
[1-5] In the compound of Formula (I) of Embodiment [1] above, R5 is preferably a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkoxycarbonyl group, a —NRbRc group (in which each of Rb and Rc independently represents a hydrogen atom, a C1-6 alkyl group or a non-aromatic heterocyclic group), a di-C1-6 alkylamino C1-6 alkyl group, a C3-8 cycloalkyl group, a C6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a C3-8 cycloalkyl C1-6 alkyl group, a C6-14 aryloxy group, a heteroaryloxy group and a C7-20 aralkyloxy group, or
more preferably a group arbitrarily selected from a halogen atom, a C1-4 alkyl group, a halogenated C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 alkoxycarbonyl group, a —NRbRc group (in which each of Rb and Rc independently represents a hydrogen atom, a C1-4 alkyl group or a 5- to 10-member non-aromatic heterocyclic group), a di-C1-4 alkylamino C1-4 alkyl group, a C3-6 cycloalkyl group, a C6-10 aryl group, a 5- to 10-member non-aromatic heterocyclic group, a 5- to 10-member heteroaryl group, a C3-6 cycloalkyl C1-4 alkyl group, a C6-10 aryloxy group, 5- to 10-member heteroaryloxy group and a C7-14 aralkyloxy group, or
still more preferably a group arbitrarily selected from a halogen atom, a C1-2 alkyl group, a halogenated C1-2 alkyl group, a C1-2 alkoxy group, a C1-4 alkoxycarbonyl group, a —NRbRc group (in which each of Rb and Rc independently represents a hydrogen atom, a C1-2 alkyl group or a 5- to 6-member non-aromatic heterocyclic group), a di-C1-2 alkylamino C1-2 alkyl group, a C3-6 cycloalkyl group, a phenyl group, a 5- to 10-member non-aromatic heterocyclic group, a 5- to 10-member heteroaryl group, a C3-6 cycloalkyl C1-2 alkyl group, a phenoxy group, a 5- to 6-member heteroaryloxy group and a C7-8 aralkyloxy group.
Each of the cycloalkyl group, aryl group, non-aromatic heterocyclic group, heteroaryl group, cycloalkylalkyl group, aryloxy group, heteroaryloxy group or aralkyloxy group in R5 above may also be substituted with 1 to 5 of a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a cyano group, a C1-6 alkoxycarbonyl group, a C3-8 cycloalkyl group, a C6-14 aryl group, a non-aromatic heterocyclic group and a heteroaryl group, and preferably with 1 to 3 of a group arbitrarily selected from a halogen atom, a C1-4 alkyl group, a halogenated C1-4 alkyl group, a C1-4 alkoxy group, a cyano group, a C1-4 alkoxycarbonyl group, a C3-6 cycloalkyl group and a 5- to 10-member non-aromatic heterocyclic group.
[1-6] In the compound of Formula (I) of Embodiment [1] above, R6 is preferably a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a cyano group, a C1-6 alkoxycarbonyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a C3-8 cycloalkyl C1-6 alkyl group, a C7-20 aralkyl group, a heteroaryl C1-6 alkyl group, a C6-14 aryloxy group, a C7-20 aralkyloxy group and a heteroaryl C1-6 alkyloxy group, or
more preferably a group arbitrarily selected from a halogen atom, a C1-4 alkyl group, a halogenated C1-4 alkyl group, a C1-4 alkoxy group, a cyano group, a C1-4 alkoxycarbonyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, a C6-10 aryl group, a 5- to 10-member non-aromatic heterocyclic group, a 5- to 13-member heteroaryl group, a C3-6 cycloalkyl C1-4 alkyl group, a C7-14 aralkyl group, a 5- to 10-member heteroaryl C1-4 alkyl group, a C6-10 aryloxy group, a C7-14 aralkyloxy group and a 5- to 10-member heteroaryl C1-4 alkyloxy group, or
still more preferably a group arbitrarily selected from a halogen atom, a C1-2 alkyl group, a halogenated C1-2 alkyl group, a C1-2 alkoxy group, a cyano group, a C1-4 alkoxycarbonyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, a phenyl group, a 5- to 10-member non-aromatic heterocyclic group, a 5- to 13-member heteroaryl group, a C3-6 cycloalkyl C1-2 alkyl group, a C7-8 aralkyl group, 5- to 10-member heteroaryl C1-2 alkyl group, a phenyloxy group, a C7-8 aralkyloxy group and a 5- to 10-member heteroaryl C1-2 alkyloxy group, and
each of the alkyl group, alkoxy group, alkoxycarbonyl group, cycloalkyl group, cycloalkenyl group, aryl group, non-aromatic heterocyclic group, heteroaryl group, cycloalkylalkyl group, aralkyl group, heteroarylalkyl group, aryloxy group, aralkyloxy group or heteroarylalkyloxy group in R6 above may be substituted with 1 to 5 of R7.
[1-7] In the compound of Formula (I) of Embodiment [1] above, R7 is preferably a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkoxy C1-6 alkyl group, a cyano group, a C1-6 alkoxycarbonyl group, a —CONRdRe group (in which each of Rd and Re independently represents a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group or a C6-14 aryl group), a mono-C2-7 alkanoylamino group, an amino group, a di-C1-6 alkylamino group, a C3-8 cycloalkyl group, a non-aromatic heterocyclic group, a C3-8 cycloalkyl C1-6 alkyl group, a non-aromatic heterocyclic C1-6 alkyl group, a C6-14 aryloxy group, a C3-8 cycloalkylcarbonyl group, a C6-14 arylcarbonyl group and a non-aromatic heterocyclic carbonyl group, or
more preferably a group arbitrarily selected from a halogen atom, a C1-4 alkyl group, a halogenated C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 alkoxy C1-4 alkyl group, a cyano group, a C1-4 alkoxycarbonyl group, a —CONRdRe group (in which each of Rd and Re independently represents a hydrogen atom, a C1-4 alkyl group, a C3-6 cycloalkyl group or a C6-10 aryl group), a mono-C2-5 alkanoylamino group, an amino group, di-C1-4 alkylamino group, a C3-6 cycloalkyl group, a 5- to 10-member non-aromatic heterocyclic group, a C3-6 cycloalkyl C1-4 alkyl group, a 5- to 10-member non-aromatic heterocyclic C1-4 alkyl group, a C6-10 aryloxy group, a C3-6 cycloalkylcarbonyl group, a C6-10 arylcarbonyl group and a 5- to 10-member non-aromatic heterocyclic carbonyl group, or
still more preferably a group arbitrarily selected from a halogen atom, C1-4 alkyl group, a halogenated C1-2 alkyl group, a C1-2 alkoxy group, a C1-2 alkoxy C1-2 alkyl group, a cyano group, a C1-4 alkoxycarbonyl group, a —CONRdRe group (in which each of Rd and Re independently represents a hydrogen atom, a C1-2 alkyl group, a C3-6 cycloalkyl group or a phenyl group), a mono-C2-3 alkanoylamino group, an amino group, di-C1-2 alkylamino group, a C3-6 cycloalkyl group, a 5- to 6-member non-aromatic heterocyclic group, a C3-6 cycloalkyl C1-2 alkyl group, a 5- to 6-member non-aromatic heterocyclic C1-2 alkyl group, a phenyloxy group, a C3-6 cycloalkylcarbonyl group, a phenylcarbonyl group and a 5- to 6-member non-aromatic heterocyclic carbonyl group, and
each of the non-aromatic heterocyclic group or cycloalkylcarbonyl group in R7 above is optionally substituted with 1 to 5 of a halogen atom, C1-6 alkyl group or C1-6 alkoxy C1-6 alkyl group.
[1-8] Examples of the pyrazole ring structure to which R1, R2 and R3 are bound in the compound of Formula (I) of Embodiment [1] above include those represented by partial structural Formula (a1), (a2), (a3), (a4) or (a5) below:
##STR00006##
(in Formula (a1), (a2), (a3), (a4) or (a5), R1 and R3 are defined as in Formula (I) above, R2a is defined in the same way as R2 in Formula (I) above except that in Formula (a1), R2a does not form a condensed cyclic group with R1 or R3 and part of the pyrazole ring,
each of G1, G2, G3, G4, G5, G6, G7 and G8 independently represents a nitrogen atom, C—H or C—R6a,
the following partial structural formula
##STR00007##
represents a 5- to 7-member non-aromatic heterocyclic group comprising one nitrogen atom and 4 to 6 carbon atoms,
each R6a independently represents a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a C6-14 aryloxy group, a heteroaryloxy group, a C7-20 aralkyloxy group and a heteroaryl C1-6 alkyloxy group, and each R6a is optionally substituted with 1 to 5 of R7a, with R7a being defined in the same way as R7 in Formula (I) above,
each R6b independently represents a group arbitrarily selected from a C1-6 alkoxycarbonyl group, a C3-8 cycloalkyl C1-6 alkyl group, a C7-20 aralkyl group and a heteroaryl C1-6 alkyl group, and each R6b is optionally substituted with 1 to 5 of R7b,
each R7b independently represents a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a cyano group, a C6-14 aryloxy group and a heteroaryloxy group, and
each R6c independently represents a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group and a cyano group, and each n1 is independently a number from 0 to 5).
More preferably, the pyrazole ring structure to which R1, R2 and R3 are bound in the compound of Formula (I) of Embodiment [1] above is represented by partial structural Formula (a1), (a2) or (a4) above, or more preferably by partial structural Formula (a2) above.
In the partial structural Formula (a2) above, all of G1, G2, G3 and G4 are preferably C—H or C—R6a, or else any one of G1, G2, G3 and G4 is a nitrogen atom. More preferably, all of G1, G2, G3 and G4 are preferably C—H or C—R6a in the partial structural Formula (a2) above, or in other words Formula (a2) represents an indazole ring structure. Still more preferably, in the partial structural Formula (a2) above, any one of G1, G2, G3 and G4 is C—R6a and the rest are C—H, and most preferably G2 is C—R6a and G1, G3 and G4 are C—H.
In the partial structural Formula (a3) above, preferably all of G5, G6, G7 and G8 are C—H or C—R6a, or else any one of G1, G2, G3 and G4 is a nitrogen atom.
In the partial structural Formula (a2) or (a3), preferably each R6a is independently a group arbitrarily selected from a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a cyano group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group, a non-aromatic heterocyclic group, a heteroaryl group, a C6-14 aryloxy group, a C7-20 aralkyloxy group and a heteroaryl C1-6 alkyloxy group, and
more preferably each is independently a group arbitrarily selected from a halogen atom, a C1-4 alkyl group, a halogenated C1-4 alkyl group, a C1-4 alkoxy group, a cyano group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, a C6-10 aryl group, a 5- to 10-member non-aromatic heterocyclic group, a 5- to 13-member heteroaryl group, a C6-10 aryloxy group, a C7-14 aralkyloxy group and a 5- to 10-member heteroaryl C1-4 alkyloxy group, and
still more preferably each is independently a group arbitrarily selected from a halogen atom, a C1-2 alkyl group, a halogenated C1-2 alkyl group, a C1-2 alkoxy group, a cyano group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, a phenyl group, a 5- to 10-member non-aromatic heterocyclic group, a 5- to 13-member heteroaryl group, a phenyloxy group, a C7-8 aralkyloxy group and a 5- to 10-member heteroaryl C1-2 alkyloxy group, and
each of the alkyl group, alkoxy group, cycloalkyl group, cycloalkenyl group, aryl group, non-aromatic heterocyclic group, heteroaryl group, aryloxy group, aralkyloxy group or heteroarylalkyloxy group in R6a above is optionally substituted with 1 to 5 of R7a.
In the partial structural Formula (a4) or (a5) above, the partial structural formula:
##STR00008##
preferably represents a non-aromatic heterocyclic group represented by a partial structural formula selected arbitrarily from:
##STR00009##
In the partial structural Formula (a4) or (a5) above, preferably each R6b is independently a group arbitrarily selected from a C1-4 alkoxycarbonyl group, a C3-6 cycloalkyl C1-4 alkyl group, a C7-14 aralkyl group and a 5- to 10-member heteroaryl C1-4 alkyl group, or
more preferably each is independently a group arbitrarily selected from a C1-4 alkoxycarbonyl group, a C3-6 cycloalkyl C1-2 alkyl group, a C7-8 aralkyl group and a 5- to 6-member heteroaryl C1-2 alkyl group.
In the partial structural Formula (a4) or (a5) above, n1 is preferably 0.
The partial structural Formula (a4) above is preferably a structural formula arbitrarily selected from the partial structural formulae (a4-1), (a4-2) and (a4-3) below:
##STR00010##
(in Formula (a4-1), (a4-2) or (a4-3), R1 and R6b are defined as in Formula (a4) above), and more preferably is Formula (a4-1) or (a4-2).
The partial structural Formula (a5) above is preferably a structural formula arbitrarily selected from the following partial structural formulae (a5-1), (a5-2), (a5-3) and (a5-4):
##STR00011##
(in Formula (a5-1), (a5-2), (a5-3) or (a5-4), R3 and R6b are defined as in Formula (a5) above).
[1-8-1] In the partial structural Formula (a2) or (a3) above, it is especially desirable that each R6a be independently a group arbitrarily selected from a halogen atom, a C1-2 alkyl group, a halogenated C1-2 alkyl group, a C1-2 alkoxy group, a C3-6 cycloalkenyl group, a phenyl group, a 5- to 10-member non-aromatic heterocyclic group and a 5- to 13-member heteroaryl group.
Each of the alkyl group, alkoxy group, cycloalkenyl group, phenyl group, non-aromatic heterocyclic group or heteroaryl group in R6a above may be substituted with 1 to 5 of R7a, and more specifically R6a is a chlorine atom, a bromine atom, methyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, pyridyl, pyrazolyl, piperidinyl, piperazinyl, 3,6-dihydro-2H-pyranyl, 1,2,3,6-tetrahydropyridyl, furo[3,2-b]pyridyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 3,4-dihyro-2H-pyrido[4,3-b][1,4]oxazinyl, 6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazinyl, 6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridyl, 2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepinyl, 7,8,9,10-tetrahydro-6H-pyrido[3,2-b][1,4]oxazocinyl, indazolyl or pyrazolo[1,5-a]pyrimidinyl group, and
R7a represents deuterium or a fluorine atom or a chlorine atom, methyl, ethyl, isopropyl, isobutyl, difluoromethyl, trifluoromethyl, methoxy, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, phenoxy, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, furo[3,2-b]pyridyl, 2-oxa-7-azaspiro[3,4]octanyl, morpholinemethyl, cyclopropylcarbonyl, tert-butoxycarbonyl (Boc), methoxyethyl, methoxymethyl, cyano, oxo or a dimethylamino group.
[2] In the compound of Formula (I) of Embodiment[1] above or its pharmaceutically acceptable salt or a solvate of these, a preferred embodiment is the compound represented by the following Formula (I)-1:
##STR00012##
(in Formula (I)-1, R1a represents a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, a cyano group, a C3-8 cycloalkyl group and a C6-14 arylcarbonyl group, and each R1a is optionally substituted with 1 to 5 halogen atoms,
R6a is defined in the same way as the R6a in the partial structural Formula (a2) of Embodiment[1] above, and each R6a is optionally substituted with 1 to 5 of R7a,
R7a is defined in the same way as the R7 of Formula (I) in Embodiment[1] above, and n represents 0, 1 or 2), or its pharmaceutically acceptable salt or a solvate of these.
In the compound of Formula (I)-1 above, n is preferably 0 or 1.
In the compound of Formula (I)-1 above, R1a may preferably be a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a cyano group, a C3-8 cycloalkyl group and a C6-14 arylcarbonyl group, or more preferably a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-4 alkyl group, a C1-4 alkoxy group, a cyano group, a C3-6 cycloalkyl group and a C6-10 arylcarbonyl group, or still more preferably a group arbitrarily selected from a hydrogen atom, a halogen atom, a C1-2 alkyl group, a C1-2 alkoxy group, a cyano group, a C3-6 cycloalkyl group and phenylcarbonyl group, and each of the alkyl group, alkoxy group, cycloalkyl group or an alkylcarbonyl group in R1a above is optionally substituted with 1 to 5 halogen atoms. In the compound of Formula (I)-1 above, the definitions and preferred ranges of R6a and R7a are as described above with respect to Embodiments [1-1] to [1-8].
[2-1] In the compound of Formula (I)-1 above, it is especially desirable that R1a be a group arbitrarily selected from a hydrogen atom and a halogen atom, and specifically that it represent a hydrogen atom or a chlorine atom.
Thus, preferred embodiments of the compound represented by Formula (I) of Embodiment[1] above may be formed at will by appropriately combining the individual aspects of Embodiments [1] and [2] of the invention and preferred embodiments thereof together with the definitions of the various substituents.
In Embodiments [1] and [2] above and their sub-aspects, more preferred substituents and combinations of substituents in Formula (I) are in accordance with the explanations given in Embodimentl.
[3] As a preferred compound of the compounds represented by Formula (I) in Embodiment[1], Embodiment 3 of the invention is a compound having one of the structures listed below, or a pharmaceutically acceptable salt thereof or a solvate of these, or an optical isomer of these.
##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##
##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096##
[3-1] In the compound of Formula (I) of Embodiment[1] above, examples of more preferred compounds include those listed below, or pharmaceutically acceptable salts thereof or solvates of these, or optical isomers of these. The names of the compounds shown below are based on English names obtained in accordance with the compound-naming program of BIOVIA Pipeline Pilot 9.5.0.831, Molecule to Chemical Name component (Name Style: IUPAC).
5-(indazol-1-yl)-1-oxo-1,2-thiazol-3-ol (Example 1);
5-(5-bromoindazol-1-yl)-1-oxo-1,2-thiazol-3-ol (Example 2);
5-[5-(2-methoxypyridin-4-yl) indazol-1-yl]-1-oxo-1,2-thiazol-3-ol (Example 3);
5-[5-(6-cyclopropylpyridin-3-yl) indazol-1-yl]-1-oxo-1,2-thiazol-3-ol (A) (Example 4); and
5-[5-(4-methyl-2, 3-dihydropyrido[3,2-b][1, 4]oxazin-7-yl)indazol-1-yl]-1-oxo-1,2-thiazol-3-ol (A) (Example 5).
[4] Embodiment 4 of the present invention is a pharmaceutical composition containing as an active ingredient at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these.
[5] Embodiment 5 of the present invention is a preventative and/or treatment agent for diseases associated with Nrf2, containing as an active ingredient at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these.
[5-1] Embodiment 5-1 of the present invention is the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these for use in preventing and/or treating a disease associated with Nrf2.
Examples of diseases associated with Nrf2 include autoimmune diseases (multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, etc.), central nervous system diseases (Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, etc.), respiratory diseases (chronic occlusive pulmonary disease, etc.), malignant tumors (melanoma, lung cancer, medulloblastoma, neuroblastoma, etc.), eye diseases (ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, etc.), skin diseases (dermatitis, radiation skin disorders, epidermolysis bullosa, etc.), kidney diseases (diabetic nephropathy, etc.), circulatory diseases (pulmonary arterial hypertension, etc.), liver diseases (hepatitis, liver cirrhosis, etc.), traumatic brain injury, aging, diabetes, obesity and the like.
[6] Embodiment 6 of the present invention is a preventative and/or treatment agent for multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, melanoma, lung cancer, medulloblastoma, neuroblastoma, chronic occlusive pulmonary disease, ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, dermatitis, radiation skin disorders, epidermolysis bullosa, diabetic nephropathy, pulmonary arterial hypertension, hepatitis, liver cirrhosis, traumatic brain injury, aging, diabetes or obesity, containing at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these as an active ingredient.
[6-1] Embodiment 6-1 of the present invention is the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these for use in preventing and/or treating multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, melanoma, lung cancer, medulloblastoma, neuroblastoma, chronic occlusive pulmonary disease, ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, dermatitis, radiation skin disorders, epidermolysis bullosa, diabetic nephropathy, pulmonary arterial hypertension, hepatitis, liver cirrhosis, traumatic brain injury, aging, diabetes or obesity.
Preferred is a preventative and/or treatment agent for multiple sclerosis or psoriasis, containing at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these as an active ingredient.
Also preferred is the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these for use in preventing and/or treating multiple sclerosis or psoriasis.
[7] Embodiment 7 of the invention is an Nrf2 activation agent comprising at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these.
[7-1] Embodiment 7-1 of the present invention is the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these for use in Nrf2 activation.
[8] Embodiment 8 of the invention is the use of at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these as a pharmaceutical composition.
[8-1] Embodiment 8-1 of the present invention is the use of at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these in the manufacture of a pharmaceutical composition.
[9] Embodiment 9 of the present invention is the use of at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these as an Nrf2 activation agent.
[9-1] Embodiment 9-1 of the present invention is the use of at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these in the manufacture of an Nrf2 activation agent.
[10] Embodiment 10 of the present invention is a method for treating a disease selected from multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, melanoma, lung cancer, medulloblastoma, neuroblastoma, chronic occlusive pulmonary disease, ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, dermatitis, radiation skin disorders, epidermolysis bullosa, diabetic nephropathy, pulmonary arterial hypertension, hepatitis, liver cirrhosis, traumatic brain injury, aging, diabetes and obesity, which is a method comprising the administration of at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these to a subject in need of treatment for such a disease or condition.
Preferably, this is a method for treating multiple sclerosis or psoriasis, which is a method comprising the administration of at least one of the compound represented by Formula (I) above or a pharmaceutically acceptable salt thereof or a solvate of these to a subject in need of treatment for such a disease or condition.
In this Description, unless otherwise specified, “treatment” as in “treatment for a disease or condition” means to cure, alleviate or suppress the progress of “diseases or conditions” or at least one or a plurality of “diseases or conditions”. Moreover, depending on the patient's condition, in this Description “treatment” encompasses preventing the occurrence of the “disease or condition” or of any symptoms associated with the “disease or condition”, as well as reducing the severity of the “disease or condition” or any symptoms thereof prior to occurrence. In this Description, “treating” is considered to include preventing or improving the reoccurrence of a “disease or condition”.
[11] Embodiment 11 of the invention is the preventative and/or treatment agent according to Embodiment [6] or the method according to Embodiment [10] in which the disease is selected from the group consisting of multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, melanoma, lung cancer, medulloblastoma, neuroblastoma, chronic occlusive pulmonary disease, ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, dermatitis, radiation skin disorders, epidermolysis bullosa, diabetic nephropathy, pulmonary arterial hypertension, hepatitis, liver cirrhosis, traumatic brain injury, aging, diabetes and obesity.
The compound of the present invention is preferably a compound with an EC50 value of not more than 10 μM with respect to Nrf2 as measured on the basis of a method, in which Nrf2 activation ability is suitably selected, for example, Pharmacological Test Example 1 below (Nrf2 activation ability evaluation). More preferably, it is a compound with an EC50 value of not more than 5 μM, or more preferably not more than 1 μM for Nrf2.
In all of the embodiments above, the word “compound” is also considered to refer also to a “pharmaceutically acceptable salt thereof”.
Moreover, in this Description unless otherwise specified descriptions of the “compound of Formula (I)”, “compound represented by Formula (I)” and the like are considered to refer also to subordinate concepts of the “compound of Formula (I)”, such as “the compound of Formula (I)-1” for example.
Depending on the kinds of substituents, the compound of the present invention may sometimes form an acid-addition salt or a salt with a base. These salts are not particularly limited as long as they are pharmaceutically acceptable, but examples include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids and the like.
These salts can be obtained by ordinary methods by first mixing the compound of the invention with a solution containing a suitable amount of an acid or base to form the target salt, and then either fractionating by filtration or distilling off the mixing solvent. Moreover, the compound of the invention or a salt thereof may also form a solvate with a solvent such as water, ethanol, glycerol or the like.
The compound of the present invention may be present in a non-solvated form or solvated form. In this Description, a “solvate” is a molecular complex containing the compound of the invention and one or more kinds of pharmaceutically acceptable solvent molecules (such as water or ethanol). When the solvent molecule is water, the solvate is called a “hydrate”.
The following descriptions of the compound of the present invention encompass descriptions relating to salts, solvates, and solvates of salts thereof.
When the compound of the present invention has isomers such as geometric isomers, configurational isomers, tautomers, optical isomers, stereoisomers, regioisomers and rotamers, any of these isomers and mixtures of these isomers are included in the compound of the invention. Moreover, when the compound of the invention has optical isomers, optical isomers that have been separated from a racemic mixture are included in the compound of the invention.
When the compound of the invention has geometric isomers, configurational isomers, stereoisomers, conformers and the like, these can each be isolated by known methods.
When the compound of the invention is optically active, it can be separated into the (+) form or (−) form [D form or L form] from the corresponding racemic mixture by ordinary optical resolution means.
The compound of the invention may also be a crystal, and both single crystal forms and crystal form mixtures are included in the compound of the invention.
The compound of the invention may also be a pharmaceutically acceptable co-crystal or co-crystal salt. A co-crystal or co-crystal salt here means a crystalline substance composed of two or more independent solids at room temperature, each having different physical properties (such as structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A co-crystal or co-crystal salt can be produced by known co-crystallization methods.
The compound of the invention also includes compounds that have been isotopically labeled or substituted with isotopes such as hydrogen isotopes (2H, 3H, etc.), carbon isotopes (11C, 13C, 14C, etc.), chlorine isotopes (36Cl, etc.), fluorine isotopes (18F, etc.), iodine isotopes (123I, 125I, etc.), nitrogen isotopes (13N, 15N, etc.), oxygen isotopes (15O, 17O, 18O, etc.), phosphorus isotopes (32P, etc.) and sulfur isotopes (35S, etc.).
[Method for Manufacturing Compound of Invention]
A method for manufacturing the compound represented by Formula (I) of the invention is explained below. A compound represented by Formula (I) that is a compound of the invention, or a salt thereof or a solvate of these, can be easily manufactured by a combination of known ordinary chemical manufacturing methods using commercial compounds or compounds easily obtained from commercial compounds by production methods known in the literature as starting materials or synthesis intermediates, and can be manufactured by the typical manufacturing methods described below. However, the present invention is in no way limited to the manufacturing methods explained below.
Unless otherwise specified, the definitions of R1, R2 and the like in the individual formulae in the manufacturing method below are the same as the corresponding definitions in Formula (I) as described in the embodiments above. Unless otherwise specified, Y in the manufacturing method is defined as a halogen atom. Unless otherwise specified, W in the manufacturing method is defined as boronic acid or a boronic acid ester, trifluoroborate salt or boronic acid N-methyliminodiacetate ester.
The formulae in each step in the manufacturing method may also form salts, and examples of these salts include the salts of Formula (I) described above. The raw material compounds in each step in the manufacturing method may be used in the following reactions either as reaction solutions or as coarse products. They may also be isolated from a reaction mixture by ordinary methods, and easily purified by separation methods that are themselves well known, such as extraction, concentration, neutralization, filtration, distillation, re-crystallization and chromatography for example.
The solvent used in the above-mentioned re-crystallization may be water, methanol, ethanol, 2-propanol, butanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, n-hexane, cyclohexane, heptane, benzene, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, chloroform, methylene chloride, 1,2-dichloroethane, acetonitrile, acetone, diphenylketone, methyl acetate, ethyl acetate, dimethylsulfoxide, acetic acid, trifluoroacetic acid, methanesulfonic acid or the like for example. These solvents may be used individually, or two or more solvents may be mixed in appropriate proportions, such as a ratio of 1:1 to 1:10 for example. When the compounds in the formulae are commercially available, the commercial products may be used as is, or the compounds may be manufactured by known methods or analogous methods.
When the individual formulae in each step in the manufacturing method include convertible functional groups (such as carboxy, amino, hydroxyl, carbonyl, mercapto, C1-6 alkoxycarbonyl, C6-14 aryloxycarbonyl, C7-20 aralkyloxycarbonyl or sulfo groups or halogen atoms or the like), these functional groups may be converted by well-known methods or analogous methods to manufacture various compounds.
In the above-mentioned conversion reactions, when a compound is obtained in a free form it may be converted into a salt by ordinary methods, while when it is obtained as a salt it may be converted into a free form or into another salt by ordinary methods.
Conversion of these functional groups may be accomplished by methods such as those described in Comprehensive Organic Transformations, 2nd Ed. (Larock, 1999, Wiley-VCH) for example.
When the various formulae in each step in the manufacturing method contain reactive groups such as hydroxyl groups, amino groups, carboxy groups, and thiol groups as substituents, these groups may be protected appropriately in each reaction step, and the protective groups may be removed at the appropriate stage.
Methods for introducing and removing protecting groups may be adapted to the type of protected group and protective group, and the methods described in Greene's Protective Groups in Organic Synthesis, 5th Ed. (Wuts, 2014, John Wiley & Song) may be followed for example.
Unless otherwise specified, the reaction temperature at each step in the manufacturing method is not restricted as long as it is within the range of from −78° C. to the reflux temperature of the solvent. Moreover, unless otherwise specified the reaction time is not limited as long as it is a time that allows the reaction to progress sufficiently.
With reference to the reaction temperature, “within the range of from −78° C. to the reflux temperature of the solvent” means a temperature within the range of from −78° C. to the temperature at which the solvent (or mixed solvent) used in the reaction undergoes refux. When the solvent is methanol for example, “at a temperature of from −78° C. to the reflux temperature of the solvent” means at a temperature in the range of from −78° C. to the temperature at which methanol undergoes reflux. Similarly, “at a temperature of from −78° C. to the reflux temperature of the reaction solution” means at a temperature in the range of from −78° C. to the temperature at which the reaction solution undergoes reflux.
The reactions in each step of the manufacturing method may be performed without a solvent, or else the raw material compounds may be dissolved or suspended before the reaction in a reaction inert solvent.
Examples of solvents that do not participate in the reaction include water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethyl phosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, propionitrile, diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, methyl acetate, ethyl acetate, butyl acetate, acetone, methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, triethylamine, N,N-diisopropylethylamine, pyridine, lutidine, acetic anhydride, formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and the like. These solvents may be used individually, or two or more different solvents may be selected appropriately according to the reaction conditions and mixed and used in suitable proportions.
Unless otherwise specified, when a “reaction inert solvent” is described in the manufacturing method it may be one kind of solvent or a mixed solvent of two or more kinds.
Examples of bases (or deacidifiers) used in each step of the manufacturing process include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogencarbonate, triethylamine, N,N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and the like. However, examples are not necessarily limited to those listed above.
Examples of acids or acid catalysts used in each step of the manufacturing method include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like. However, examples are not necessarily limited to those listed above.
The compound represented by Formula (I) in the present invention can be obtained from a substitution reaction of the heterocyclic ring represented by Formula (HA) and the isothiazole ring represented by Formula (IT).
##STR00097##
Methods for manufacturing the compound represented by Formula (I) are shown below.
<Manufacturing Method A>
##STR00098##
The compound of Formula (I) can be manufactured using the compound of Formula (HA) [the compound of Formula (HA) is a commercial compound or a compound that can be manufactured from commercial compounds by methods known in the literature or by Step 3 of Manufacturing Method B or Step 3 of Manufacturing Method C below] and the compound of Formula (IT) [the compound of Formula (IT) is a compound that can be manufactured by methods known in the literature, such as for example “Manufacturing Method I” or “Reference Example 1” of WO 2012/147518] by performing a reaction with or without a base such as sodium hydride, sodium hydroxide, potassium carbonate, triethylamine or pyridine in a solvent that does not affect the reaction, such as diethyl ether, tetrahydrofuran, benzene, toluene, N,N-dimethylformamide, dichloromethane or chloroform, at a temperature between 0° C. and the reflux temperature of the solvent, in accordance with a known method such as the method described in “Jikken Kagaku Koza, the fourth edition (The Fourth Series of Experimental Chemistry). 20, Organic Synthesis II, alcohols and amines, pp. 187-200 and pp. 284-292, 1992, Maruzen” and “Jikken Kagaku Koza, the fourth edition (The Fourth Series of Experimental Chemistry). 20, Organic Synthesis VI, Hetero elements and typical metal element compounds, pp. 319-350, 1992, Maruzen”.
<Manufacturing Method B>
<When any of R1, R2 and R6 in Formula (I) above is a cyclic group, or in other words when Formula (I) is represented by Formula (Ia):
##STR00099##
(in which ring A represents a pyrazole ring or fused ring partially having a pyrazole ring, and when ring A is a pyrazole ring, ring A is substituted with R1, R2 and R3, and ring B represents a cyclic group of R1 or R2, while when ring A is a fused ring partially having a pyrazole ring, ring A is substituted with R1 or R3 and 1 to 5 of R6, and B represents a cyclic group of R6), and ring B binds to a carbon atom of ring A>
##STR00100##
<Step 1>
The compound of Formula (B-II) can be manufactured using the compound of Formula (IT) and the compound of Formula (B-I) [the compound of Formula (B-I) is a commercial compound or a compound that can be manufactured by methods known in the literature from commercial compounds] by performing a reaction in accordance with Manufacturing Method A.
<Step 2>
Using the compound of Formula (B-II) obtained in Step 1 of Manufacturing Method B and the compound of Formula (B-III) [the compound of Formula (B-III) is a commercial compound or a compound that can be manufactured by methods known in the literature from commercial compounds], the compound represented by Formula (1a) can be manufactured in accordance with the methods described in known literature, such as for example the methods described in “Jikken Kagaku Koza, the fifth edition (The Fifth Series of Experimental Chemistry). 18, Synthesis of Organic Compounds VI, Organic synthesis using metals, pp. 327-352, 2004, Maruzen” and “Journal of Medicinal Chemistry, 48(20), 6326-6339, 2005”, by performing a reaction in the presence of a palladium catalyst such as palladium (II)acetate (Pd(OAc)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), tris(dibenzilideneacetone)dipalladium (Pd2(dba)3), bis(dibenzylideneacetone)palladium (Pd(dba)2) or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (PdCl2(dppf)), a phosphine reagent such as triphenylphosphine, tris(tert-butyl)phosphine, tris(o-tolyl)phosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, or 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, and an organic or inorganic base such as triethylamine, N,N-diisopropylethylamine, potassium phosphate, potassium carbonate or cesium carbonate, in a solvent that does not affect the reaction, such as toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethoxyethane, acetonitrile (acetonitrile/water), dioxane (dioxane/water), tetrahydrofuran (tetrahydrofuran/water) or a mixed solvent of these, at a temperature between 0° C. and the reflux temperature of the solvent. It can also be manufactured by a similar reaction using tetramethylammonium chloride, tetrabutylammonium chloride or the like in place of the phosphine reagent.
<Step 3>
The compound of Formula (B-IV) can be manufactured by performing a reaction in accordance with Step 2 of Manufacturing Method B using the compound of Formula (B-I) and the compound of Formula (B-III) [the compound of Formula (B-III) is a commercial compound or a compound that can be manufactured from commercial compounds by methods known in the literature].
<Step 4>
The Compound of Formula (1a) can be manufactured by performing a reaction in accordance with Manufacturing Method A using the compound of Formula (B-IV) obtained in Step 3 of Manufacturing Method B and the compound of Formula (IT).
<Manufacturing Method C>
<When the pyrazole ring structure to which R1, R2 and R3 are bound in Formula (I) above is represented by the partial structural Formula (a4) or (a5) above, and R6b is a C3-8 cycloalkylmethyl group, C6-14 arylmethyl group or heteroarylmethyl group, or in other words when Formula (I) is represented by Formula (Ib):
##STR00101##
(in which ring A′ represents a fused ring part consisting of the non-aromatic heterocyclic ring and pyrazole ring in the partial structural Formula (a4) or (a5), or in other words (a4′) or (a5′):
##STR00102##
a nitrogen atom on ring A′ is substituted with a cyclic C-methyl group, ring C represents a C3-8 cycloalkyl group, C6-14 aryl group or heteroaryl group, and ring C may be substituted with 1 to 5 of R7b)>
##STR00103##
<Step 1>
The compound of Formula (C-II) can be manufactured by performing a reaction in accordance with Manufacturing Method A using the compound of Formula (C-1) [the compound of Formula (C-1) is a commercial compound or a compound that can be manufactured from commercial compounds by methods known in the literature] and the compound of Formula (IT).
<Step 2>
Using the compound of Formula (C-II) obtained in Step 1 of Manufacturing Method C and the compound of Formula (C-III) [the compound of Formula (C-III) is a commercial compound or a compound that can be manufactured by methods known in the literature from commercial compounds], the compound represented by Formula (Ib) can be manufactured by methods described in known literature, such as for example “Journal of Medicinal Chemistry, 23(12), 1405-1410, 1980”, by performing a reaction using a reaction inert solvent such as a halogen solvent such as dichloromethane or chloroform, an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, an aromatic hydrocarbon solvent such as benzene or toluene, or a mixed solvent of these, at a temperature between 0° C. and the reflux temperature of the solvent to form an imine, and then performing another reaction in the presence of sodium borohydride in a solvent that does not participate in the reaction, such as an alcohol solvent such as methanol, ethanol or 2-propanol or an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, or a mixed solvent of these, at a temperature between 0° C. and the reflux temperature of the solvent.
The compound of Formula (1 b) can also be manufactured using the compound (C-II) obtained in Step 1 of Manufacturing Method C and the compound (C-III) by the methods described in “The Journal of Organic Chemistry, 61, 3849-3862, 1996” for example by performing a reaction at a temperature between 0° C. and the reflux temperature of the solvent in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, with or without a catalytic amount of acetic acid, in a reaction inert solvent such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, toluene, methanol, ethanol or 2-propanol, or a mixed solvent of these.
<Step 3>
The compound of Formula (C-IV) can be manufactured by performing a reaction using the compound of Formula (C-I) and the compound of Formula (C-III) in accordance with Step 2 of Manufacturing Method C.
<Step 4>
The compound of Formula (Ib) can be manufactured by performing a reaction using the compound of Formula (C-IV) obtained in Step 3 of Manufacturing Method C and the compound of Formula (IT) in accordance with Manufacturing Method A.
[Formulating Preventative and/or Treatment Agent of Invention]
The drug of the present invention is administered in the form of a pharmaceutical composition.
The pharmaceutical composition of the present invention may be any that contains at least one or more of the compound represented by Formula (I) of the invention, optionally combined with any pharmaceutically acceptable additives. More specifically, various dosage forms can be obtained by combining the compound of the invention with suitable kinds of commonly-used additives or solvents, such as excipients (for example, lactose, white sugar, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch), binders (including celluloses such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose, crystal cellulose, sugars such as lactose, mannitol, white sugar, sorbitol, erythritol and xylitol, starches such as corn starch and potato starch, pregelatinized starch, dextrin, polyvinylpyrrolidone, macrogol and polyvinyl alcohol), lubricants (such as magnesium stearate, calcium stearate, talc and carboxymethyl cellulose), disintegrants (including starches such as corn starch and potato starch, and carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium and crospovidone), coating agents (for example, celluloses such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose, and aminoalkyl methacrylate copolymer E and methacrylic acid copolymer LD), plasticizers (such as triethyl citrate and macrogol), concealing agents (such as titanium oxide), colorants, flavorings, antiseptics (such as benzalkonium chloride and paraoxybenzoic acid ester), isotonic agents (such as glycerin, sodium chloride, calcium chloride, mannitol and glucose), pH adjusters (such as sodium hydroxide, potassium hydroxide, sodium carbonate, hydrochloric acid, sulfuric acid, and buffers such as phosphate buffers), stabilizers (such as sugars, sugar alcohols and xanthan gum), dispersants, antioxidants (such as ascorbic acid, butyl hydroxy anisole, propyl gallate and d1-α-tocopherol), buffers, preservatives (such as paraben, benzyl alcohol and benzalkonium chloride), aromatics (such as vanillin, 1-menthol and rose oil), solubilizing agents (such as polyoxyethylene hardened castor oil, polysorbate 80, polyethylene glycol, phospholipid cholesterol and triethanolamine), absorption enhancers (such as sodium glycolate, sodium edetate, sodium caproate, acylcarnitine and limonene), gelling agents, suspension agents or emulsifiers.
Examples of various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, troches, liquids, alcoholic preparations, suspension, extracts, elixirs, eye drops and the like. The drug of the present invention may also be administered to a patient by oral, subcutaneous, intramuscular, intranasal, percutaneous, intravenous, intraarterial, perineural, epidural, intrathecal, intracerebroventricular, intrarectal, inhalation, intravitreal, intracameral, subconjunctival, Tenon's capsule or ophthalmic administration or the like.
The present invention is explained in detail below with examples, but the present invention is in no way limited to these.
The following Pharmacological Test Examples 1 to 7 present methods for testing the efficacy of the compounds of the present invention.
HEK293 cells constantly expressing Nrf2d-LacZ (human Nrf2 degron region fused to LacZ; Hirotsu et al, Genes to Cell, Vol. 16, pp. 406-415 (2011)) and human Keap1 were seeded 7,000 cells/27 μl/well on 384-well plates (Corning 384 Well Flat Clear Bottom White Polystyrene TC-Treated Microplates, Cat. #3707), and cultured overnight at 5% CO2, 37° C. in DMEM medium containing 10% FBS, 100 U/mL penicillin and 100 μg/mL streptomycin. 3 μL/well of a 0.1% DMSO solution of the compound of the invention was added to the cells, which were then cultured for 3 hours at 5% CO2, 37° C. Beta-Glo® reagent (Promega, Beta-Glo Assay System, Cat. #E4740) was added 15 μL/well and incubated for 1 hour at room temperature, and luminescence intensity was measured with a luminometer. Using CDDO-Im as a standard, Nrf2 activation ability was calculated given 100% as the luminescence under stimulus with 100 nM CDDO-Im.
The Nrf2 activation ability of the test compound is represented as an EC50 value, and the results of the test examples below are given in Table 2, with compounds with an EC50 value of less than 1 μM rated as A, those with EC50 values of at least 1 μM and less than 5 μM rated as B and those with EC50 values of at least 5 μM and less than 10 μM rated as C.
(1) DMSO Precipitation Solubility (Kinetic Solubility)
A 10 mM DMSO solution of the compound of the invention is added to 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 μM. This solution is incubated with stirring at 600 rpm for 1.5 hours at room temperature, then filtered with filter plate, and the absorbance of the filtrate is measured at the maximum absorption wavelength. At the same time, absorbance is measured using DMSO solutions of the test compound at known concentrations (such as 1, 3, 10, 30, and 100 μM) as standard solutions, and the solubility (μM) of the test compound is calculated from the absorbance values of a calibration curve.
(2) Crystal Solubility (Thermodynamic Solubility)
The compound of the invention is added to a solvent (such as water or buffer) to a concentration of 1 mg/mL. This solution is incubated for 24 hours at 25° C. or 37° C. with stirring at 1,000 rpm, and then filtered with filter plate. The filtrate is analyzed by HPLC, a peak is detected at the maximum absorption wavelength, and the peak area is measured. Similarly, the peak areas are measured using solutions (in DMSO, 1,4-dioxane or methanol for example) of the test compound with known concentrations (such as 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 μg/mL) as standard solutions, and the solubility (μg/mL) of the test compound is calculated from the peak areas of the calibration curve.
A 10 mM DMSO solution of the test compound is added to a liver microsome (human, rat, mouse, dog, monkey, etc.)/NADPH-generating system (β-NADP, glucose-6-phosphate, G-6-PDH(Y), aqueous solution containing MgCl2) to a final concentration of 1 μM. This solution is incubated for an appropriate time (such as 5, 10, 20 or 30 minutes) at 37° C., and the reaction is stopped by addition of acetonitrile. The reaction solution is filtered with filter plate, and the test compound in the filtrate is measured by high-performance liquid chromatographwith mass spectrometry (HPLC/MS). Similarly, a sample of 0 minute reaction time is measured as a control, and the residual rate (%) is calculated at each time point. The reaction times are plotted on the vertical axis and the residual rates on the horizontal axis, and the clearance (μl/min/mg protein) is calculated from the slope.
Similarly metabolic stability tests of the compound of the invention can be performed using hepatic cell suspensions (human, rat, dog, monkey, etc.).
The effect on the hERG (human ether-a-go-go related gene) channel can be confirmed by measuring the hERG IKr current of hERG-expressing cells using a fully-automated patch clamp system.
The compound of the invention is administered orally to rats (7- or 8-week-old male CD(SD)IGS Jcl) at a dose of 1 mg/kg (administration solvent of DMSO:Tween80:ultrapure water=1:1:8, 10 mL/kg), and after 0.5, 1, 2 and 4 hours blood is taken from the abdominal vena cava. The test compound in plasma is then measured by HPLC/MS. Standard solutions of the test compound at known concentrations are also measured in the same way, the plasma concentrations (μg/mL) are calculated from the calibration curve, and the maximum plasma concentration is given as Cmax (μg/mL).
Similarly, the compound of the invention is also administered (intravenously or orally) to animals such as male beagles and male cynomolgus monkeys, and the plasma concentrations of the test compound are measured to evaluate PK profiles in other animal species.
A 10 mM DMSO solution of the compound of the invention is added to normal plasma (human, rat, dog, monkey, etc.) to a final concentration of 10 μM. This is dialyzed for 4 hours at 37° C. in an equilibrium dialyzer, and the concentrations of the test compound in the plasma side and those in PBS side solutions are measured by HPLC/MS. The unbonded fraction (%) is calculated from the ratio of the PBS side and the serum side, and the protein binding rate (%) is calculated as 100−unbonded fraction (%).
When the compound of the invention is administered orally one time to mice or rats, there is no mortality, and no obvious behavioral abnormalities are observed, indicating that the compound of the invention is safe.
These results have shown that the compound of the invention has excellent Nrf2 activation ability. Moreover, it is confirmed from the above tests that the compound of the invention is favorable in terms of solubility, metabolic stability, avoidance of hERG channel inhibition, pharmacokinetics, protein binding, safety and the like.
Consequently, the compound of the invention is expected, as a Nrf2 activator, preferably to be useful as a preventative and/or treatment agent for diseases associated with Nrf2, or in other words for diseases including autoimmune diseases (multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, etc.), central nervous system diseases (Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, etc.), respiratory diseases (chronic occlusive pulmonary disease, etc.), malignant tumors (melanoma, lung cancer, medulloblastoma, neuroblastoma, etc.), eye diseases (ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, etc.), skin diseases (dermatitis, radiation skin disorders, epidermolysis bullosa, etc.), kidney diseases (diabetic nephropathy, etc.), circulatory diseases (pulmonary arterial hypertension, etc.), liver diseases (hepatitis, liver cirrhosis, etc.), and traumatic brain injury, aging, diabetes, obesity and the like.
Preferably the compound of the invention is expected to exhibit the desired preventative or therapeutic effect against the various diseases shown below. Specifically, it is expected to have the desired therapeutic effect against multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, melanoma, lung cancer, medulloblastoma, neuroblastoma, chronic occlusive pulmonary disease, ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, dermatitis, radiation skin disorders, epidermolysis bullosa, diabetic nephropathy, pulmonary arterial hypertension, hepatitis, liver cirrhosis, traumatic brain injury, aging, diabetes, obesity and the like.
Examples for explaining the present invention in further detail are given next, but these are only examples that do not limit the present invention, and may be changed to the extent that the changes do not deviate from the scope of the present invention.
A JEOL JNM-ECX400 FT-NMR (Jeol Resonance Inc.) or JEOL JNM-ECX300 FT-NMR (Jeol Resonance Inc.) was used for nuclear magnetic resonance spectroscopy (NMR).
In the 1H-NMR data, s in the NMR signal pattern represents a singlet, d is a doublet, t is a triplet, q is a quartet, m is a multiplex, br means broad, J is a coupling constant, Hz means hertz, CDCl3 represents deuterated chloroform, and DMSO-d6 represents deuterated dimethylsulfoxide. In the 1H-NMR data, no data is given for signals that cannot be confirmed in broadband, such as protons of hydroxyl groups, amino groups and carboxyl groups.
Liquid-chromatography-mass spectrometry spectrum (LC-Mass) was measured by any of the following methods. [UPLC][Method A] Using a Waters UPLC-ZQ MS system (Waters.) and a column (2.1 mm×5 cm, 3 μm) (Shiseido Company, Limited), the mobile phase was methanol:0.05% trifluoroacetic acid aqueous solution with a gradient condition of 5:95 (0 min) to 100:0 (1 min) to 100:0 (2 min). [LCMS] Using a Waters FractionLynx MS System (Waters.) and a SunFire column (4.6 mm×5 cm, 5 μm) (Waters.), the mobile phase [Method B] was methanol:0.05% trifluoroacetic acid aqueous solution with a gradient condition of 10:90 (0 min) to 100:0 (5 min) to 100:0 (7 min), or [Method C] methanol:0.05% acetic acid aqueous solution with a gradient condition of 10:90 (0 min) to 100:0 (5 min) to 100:0 (7 min), or [Method D] methanol:0.05% trifluoroacetic acid aqueous solution with a gradient condition of 0:90 (0 min) to 100:0 (2.0 min) to 100:0 (3.0 min) to 10:90 (4.5 min) or [Method E] methanol:0.05% acetic acid aqueous solution with a gradient condition of 0:90 (0 min) to 100:0 (2.0 min) to 100:0 (3.0 min) to 10:90 (4.5 min). The gradient conditions in the preparative system were changed appropriately according to the compound.
In the LC-Mass data, the measurement methods of each example are designated as A for “UPLC [Method A]”, B for “LCMS [Method B]”, C for “LCMS [Method C]”, D for “LCMS [Method D]” and E for “LCMS [Method E]”. In the LC-Mass data, MS-ESI means electrospray ionization mass spectrometry, M means molecular weight, RT means retention time, and [M+H]+ and [M+Na]+ represent molecular ion peaks.
“Room temperature” in the examples and manufacturing examples means the temperature in the laboratory, which is normally 20±15° C.
A compound synthesized using enantiomer A (Reference Example 1 (A) of the 5-chloro-1-oxo-1,2-thiazol-3-ol(5-chloroisothiazol-3-ol 1-oxide) described in Reference Example 1 of WO 2012/147518 is designated with an (A) after the compound name or in the structure field of Table 2. A compound synthesized using enantiomer B (Reference Example 1 (B)) is designated with a (B) after the compound name or in the structure field of Table 2. When racemic 5-chloro-1-oxo-1,2-thiazol-3-ol is used, r is given in the structure field of Table 2.
60% sodium hydride (10.6 g) was added to a tetrahydrofuran (600 mL) solution of 1H-indazole (15.6 g), and stirred for 30 minutes at 20° C., after which 5-chloro-1-oxo-1,2-thiazol-3-ol (20 g) was added and stirred for 16 hours. Water (20 mL) and 12 N hydrochloric acid aqueous solution (300 mL) were added to the reaction solution, which was then extracted three times with ethyl acetate (200 mL), washed with saturated saline (20 mL), and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and acetone (300 mL) was added to solidify the residue and obtain the title compound (9.3 g) as a yellow solid.
60% sodium hydride (2.64 g) was added to a tetrahydrofuran (150 mL) solution of 5-bromo-1H-indazole (6.5 g) and 5-chloro-1-oxo-1,2-thiazol-3-ol (5 g), and stirred for 2.5 hours at 60° C. Water (300 mL) was added to the reaction solution, which was then washed twice with ethyl acetate (300 mL), after which 1 N hydrochloric acid aqueous solution was added to the water layer to lower the pH to 3 and precipitate a solid. The precipitated solid was collected by filtration, and washed twice with ethyl acetate (300 mL) to obtain the title compound (5.7 g) as a yellow solid.
2-methoxypyridin-4-boronic acid (1.15 g), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (0.47 g), potassium carbonate (4.78 g) and bis(dibenzylideneacetone) palladium (0.33 g) were added to a solution of the 5-(5-bromoindazol-1-yl)-1-oxo-1,2-thiazol-3-ol (1.8 g) synthesized in Example 2 in a mixture of 1,4-dioxane (60 mL) and water (20 mL), and stirred for 2 hours at 100° C. Water (10 mL) was added to the reaction solution, which was then washed with ethyl acetate (5 mL). 1 N hydrochloric acid aqueous solution (5 mL) was added to the water layer to make it acidic, and this was extracted with ethyl acetate, washed sequentially with water and saturated saline, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.67 g) as a brown solid.
60% sodium hydride (260 mg) was added to a tetrahydrofuran (30 mL) solution of a 5-chloro-1-oxo-1,2-thiazol-3-ol enantiomer (Reference Example 1 (A) described in WO 2012/147518 (Reference Example 1 (A)) (500 mg) and 5-bromo-1H-indazole (650 mg), and stirred for 16 hours at 60° C. Water was added to the reaction solution, which was then washed with ethyl acetate, after which 1 N hydrochloric acid aqueous solution was added to the water layer to make it acidic and precipitate a solid. The precipitated compound was collected by filtration and washed with ethyl acetate to obtain the title compound (650 mg) as a brown solid.
2-dicyclohexylphosphino-2′,-6′-dimethoxy-1-1′-biphenyl (47 mg), potassium carbonate (480 mg) and bis(dibenzylidenedacetone) palladium (33 mg) were added to a solution of the 5-(5-bromoindazol-1-yl)-1-oxo-1,2-thiazol-3-ol (A) (180 mg) obtained in Step 1 of Example 4 and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (280 mg) dissolved in a mixed solvent of 1,4-dioxane (4.0 ml) and water (2.0 ml), and stirred for 18 hours at 100° C. Water was added to the reaction solution, which was then washed with ethyl acetate, and 1 N hydrochloric acid aqueous solution was added to the water layer to make it acidic and precipitate a solid. The precipitated compound was collected by filtration and washed with ethyl acetate to obtain the title compound (31 mg) as a brown solid.
Potassium carbonate (770 mg) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane adduct (92 mg) were added to a solution of the 5-(5-bromoindazol-1-yl)-1-oxo-1,2-thiazol-3-ol (A) (350 mg) obtained in Step 1 of Example 4 and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (620 mg) dissolved in a mixed solvent of 1,4-dioxane (3 ml) and water (1.5 ml), and stirred for 2 hours at 100° C. Water was added to the reaction solution, which was then washed with ethyl acetate, and 1 N hydrochloric acid aqueous solution was added to the water layer to make it acidic and precipitate a solid. The precipitated compound was collected by filtration and washed with ethyl acetate to obtain the title compound (245 mg) as a brown solid.
The 1H-NMR data (unmarked: 400 MHz NMR, marked *: 300 MHz NMR) for the final compounds and intermediate compounds of Examples 1 to 5 are shown in Table 1 below.
TABLE 1
Example
NMR data (δ: ppm) <*300 MHz>
1
1H-NMR (DMSO-d6*) δ: 11.14 (s, 1H), 8.70 (d, 1H,
J = 1.0 Hz), 8.18 (dd, 1H, J = 8.4, 1.0 Hz),
7.98-8.01 (m, 1H), 7.66-7.72 (1H, m), 7.45-7.51
(m, 1H), 7.03 (s, 1H)
2
1H-NMR (DMSO-d6) δ: 11.23 (s, 1H), 8.67 (s, 1H),
8.26 (d, 1H, J = 1.5 Hz), 8.18 (d, 1H, J = 8.9 Hz),
7.80 (dd, 1H, J = 8.9, 1.5 Hz), 7.09 (s, 1H)
3
1H-NMR (DMSO-d6*) δ: 11.19 (s, 1H), 8.77 (s, 1H),
8.42-8.43 (m, 1H), 8.26-8.32 (m, 2H), 8.08 (dd, 1H,
J = 8.9, 1.7 Hz), 7.44 (dd, 1H, J = 5.3, 1.5 Hz),
7.24-7.25 (m, 1H), 7.13 (s, 1H), 3.92 (s, 3H)
4-1
1H-NMR (DMSO-d6); 11.2 (brs, 1H), 8.66
(d, 1H, J = 3.0 Hz), 8.26 (d, 1H, J = 1.5 Hz), 8.18
(1H, d, J = 9.0 Hz), 7.81 (1H, dd, J = 1.5, 9.0 Hz),
7.08 (s, 1H)
4
1H-NMR (DMSO-d6); 11.2 (brs, 1H), 8.81 (d, 1H,
J = 2.5 Hz), 8.73 (s, 1H), 8.27-8.29 (m, 2H), 8.05 (dd, 1H,
J = 3.0, 8.5 Hz), 7.99 (dd, 1H, 1.5, 8.5 Hz), 7.43 (d, 1H,
J = 8.5 Hz), 7.07 (s, 1H), 2.16-2.19 (m, 1H), 0.97-1.01
(m, 4H)
5
1H-NMR (DMSO-d6); 11.1 (brs, 1H), 8.67 (s, 1H),
8.19 (1H, d, J = 8.5 Hz), 8.15 (d, 1H, J = 2.0 Hz), 8.11
(d, 1H, J = 2.0 Hz), 7.90 (dd, 1H, J = 2.0, 8.5 Hz), 7.37
(d, 1H, J = 2.0 Hz), 7.01 (s, 1H), 4.27 (t, 2H, J = 4.0 Hz),
3.49 (t, 2H, J = 4.0 Hz), 3.08 (s, 3H)
The compounds of Examples 6 to 461 under Embodiment [3] above were synthesized using commercial compounds or known compounds, in accordance with methods similar to those used in Example 4 or Example 5 or analogous methods.
The LC-Mass data, mass measurement method (method), isothiazole ring isomer structure (structure) and pharmacological activity value (EC50) for the final compounds of Examples 1 to 461 are given in Table 2 below.
For the activity values in Table 2, EC50 values measured by the methods of Pharmacological Test Example 1 are rated as A (EC50<1 μM), B (1 μM EC50<5 μM) or C (5 μM≤EC50<10 μM).
TABLE 2
MS-ESI
(m/z)
RT
Example
[M + H]+
(min)
Method
Structure
EC50
1
234
0.78
A
r
B
2
312
0.91
A
r
A
3
341
0.93
A
r
A
4
351
0.71
A
A
A
5
382
0.72
A
A
A
6
355
0.89
A
r
B
7
312
3.20
D
r
B
8
410
0.79
A
r
A
9
342
1.03
A
A
B
10
382
0.75
A
A
A
11
274**
0.8
A
r
B
12
268
0.89
A
r
A
13
312
0.89
A
r
14
302
0.93
A
r
A
15
282
0.98
A
r
B
16
234
0.77
A
A
B
17
234
0.77
A
B
C
18
262
0.93
A
r
A
19
281**
0.7
A
r
B
20
277
0.61
A
r
21
293
0.93
A
r
B
22
406
1.09
A
r
B
23
248
0.88
A
r
B
24
264
0.84
A
r
B
25
248
0.88
A
r
C
26
340
1.05
A
r
B
27
274
0.97
A
r
B
28
310
1.05
A
r
B
29
268
0.93
A
r
B
30
340
1.07
A
r
C
31
268
0.88
A
r
B
32
248
0.88
A
r
B
33
302
0.92
A
r
B
34
248
0.92
A
r
B
35
302
1.00
A
r
36
264
0.80
A
r
37
268
0.90
A
r
B
38
311
0.59
A
r
A
39
350
0.98
A
r
A
40
344
1.03
A
r
A
41
312
0.76
A
r
B
42
316
0.89
A
r
A
43
311*
0.69
A
r
A
44
415
1.08
A
r
A
45
326
0.65
A
r
B
46
351
0.71
A
r
A
47
341
0.61
A
r
B
48
316*
0.59
A
r
49
325
0.65
A
r
A
50
314
0.84
A
r
A
51
300
0.8
A
r
C
52
409*
0.67
A
r
A
53
409*
0.67
A
A
A
54
311
0.61
A
A
A
55
264
0.73
A
r
A
56
325
0.65
A
A
A
57
363
0.84
A
r
58
311
0.6
A
r
A
59
396
0.68
A
r
A
60
341*
0.6
A
r
61
351
0.9
A
r
A
62
417
1.07
A
r
A
63
411
0.96
A
r
C
64
377
0.91
A
r
B
65
407
0.91
A
r
C
66
367
0.91
A
r
B
67
367
0.92
A
r
68
393
0.92
A
r
B
69
342
0.96
A
r
B
70
312
0.83
A
r
A
71
445
3.6
D
r
B
72
311*
3.17
E
A
A
73
375
1.1
A
r
A
74
402
1.17
A
r
A
75
407
0.95
A
r
B
76
364
0.97
A
r
B
77
409
0.72
A
r
A
78
310
1.04
A
r
B
79
310
1.05
A
r
B
80
312
0.79
A
r
81
312
0.77
A
r
C
82
312
4.38
B
r
A
83
328
1.03
A
r
A
84
328
1.04
A
r
A
85
328
1.04
A
r
A
86
341
0.96
A
r
A
87
380
0.73
A
r
B
88
350
0.68
A
r
89
312
4.38
B
A
A
90
394
0.76
A
r
A
91
382
0.72
A
r
A
92
311
0.64
A
r
B
93
350
1.01
A
r
B
94
344
1.06
A
r
95
316
0.89
A
r
C
96
437**
1.08
A
r
97
341
0.96
A
r
B
98
351
0.75
A
r
B
99
341
0.60
A
r
100
325
0.66
A
r
B
101
314
0.85
A
r
B
102
350
1.02
A
r
B
103
316
0.90
A
r
B
104
437**
1.08
A
r
B
105
314
0.87
A
r
106
380
0.72
A
r
B
107
380
0.7
A
r
B
108
336
0.89
A
r
B
109
311
0.63
A
r
110
341
0.95
A
r
B
111
351
0.72
A
r
B
112
341
0.63
A
r
113
325
0.66
A
r
C
114
311
0.61
A
r
115
311
0.59
A
r
116
361
0.98
A
r
A
117
325
0.64
A
r
A
118
326
0.89
A
r
B
119
329
0.93
A
r
B
120
336
0.93
A
r
B
121
345
1.01
A
r
B
122
352
1
A
r
B
123
326
0.88
A
r
A
124
341
0.95
A
r
A
125
327
0.75
A
r
B
126
396
0.71
A
r
B
127
342
0.86
A
r
128
326
0.77
A
r
129
341
1.05
A
r
A
130
379
1.04
A
r
A
131
394
0.98
A
r
132
379
1.05
A
r
A
133
403
0.87
A
r
134
341
0.65
A
r
135
380
0.75
A
r
A
136
354
0.68
A
r
A
137
317*
0.61
A
r
138
380
0.74
A
r
A
139
380
0.79
A
r
A
140
395
1.11
A
r
A
141
381
1.06
A
r
A
142
397
0.96
A
r
B
143
396
0.75
A
r
A
144
341
4.17
B
r
B
145
327
0.78
A
r
146
354
0.69
A
r
147
396
0.69
A
r
148
326
5.43
B
r
B
149
408
0.74
A
r
A
150
422
0.83
A
r
A
151
472
5.27
B
r
A
152
368
3.57
B
r
B
153
394
0.8
A
r
A
154
382
0.83
A
r
155
352
0.69
A
r
156
380
0.84
A
r
157
408
0.9
A
r
B
158
366
0.7
A
A
A
159
442
1.01
A
A
C
160
424
0.85
A
r
A
161
422
3.47
B
r
A
162
436
5.88
B
r
A
163
388
0.86
A
A
164
394
0.94
A
A
C
165
382
0.81
A
A
B
166
341
0.74
A
A
B
167
355
0.75
A
A
B
168
421
0.96
A
A
C
169
416
5.63
B
A
A
170
450
1.03
A
A
B
171
341
0.79
A
A
C
172
426
0.78
A
A
A
173
384
0.74
A
A
A
174
412
0.8
A
A
B
175
410
0.75
A
A
A
176
424
0.79
A
A
B
177
342
0.97
A
A
A
178
382
0.97
A
A
A
179
382
0.94
A
A
A
180
424
0.82
A
A
A
181
410
0.75
A
A
B
182
416
0.77
A
A
A
183
304
1.01
A
A
B
184
407
5.08
B
A
A
185
396
3.85
B
A
A
186
394
0.95
A
A
A
187
424
1.05
A
A
A
188
410
0.8
A
A
A
189
396
0.8
A
A
A
190
382
0.75
A
A
A
191
264
4.28
C
A
B
192
412
0.81
A
A
A
193
410
0.79
A
A
A
194
410
0.79
A
A
A
195
355
0.76
A
A
B
196
278
4.73
B
A
B
197
396
4.95
B
A
A
198
424
3.9
B
A
A
199
341
4.55
B
A
B
200
341
4.22
B
A
B
201
371
5.45
B
A
A
202
371
3.18
B
A
203
381
5.3
B
A
A
204
432
1.03
A
A
A
205
410
4.63
B
A
A
206
396
3.85
B
A
A
207
342
0.95
A
A
A
208
459*
5.10
B
A
209
396
0.76
A
A
A
210
383
4.68
C
A
A
211
412
0.75
A
A
A
212
408
0.75
A
A
A
213
410
0.78
A
A
A
214
383
4.18
B
A
215
383
4.62
B
A
A
216
422
5.32
B
A
B
217
396
0.79
A
A
A
218
397
4.38
B
A
B
219
368
3.08
B
A
A
220
369
4.53
B
A
A
221
407
5.90
C
A
B
222
382
3.23
B
A
A
223
412
0.82
A
A
B
224
364
5.4
B
A
A
225
351
0.92
A
A
A
226
314
0.85
A
A
A
227
269
0.77
A
r
B
228
235
0.6
A
r
229
249
0.56
A
r
B
230
235
2.22
B
r
231
235
0.53
A
r
C
232
269
0.7
A
r
233
311
0.92
A
r
A
234
313
0.76
A
r
B
235
312
0.57
A
r
B
236
317
0.8
A
r
B
237
352
0.67
A
r
A
238
235
0.72
A
r
B
239
285
4.75
B
r
A
240
381
0.7
A
r
B
241
395
0.75
A
r
B
242
265
0.76
A
A
A
243
383*
0.69
A
A
A
244
375**
0.96
A
A
B
245
347**
0.9
A
A
B
246
347**
0.92
A
A
B
247
361**
0.9
A
A
B
248
361**
0.91
A
A
B
249
375**
0.89
A
A
250
376**
0.92
A
A
B
251
487**
1.01
A
A
C
252
329*
0.54
A
A
B
253
343
0.76
A
A
254
343
0.79
A
A
255
315*
0.53
A
A
B
256
329*
0.53
A
A
B
257
335*
0.62
A
A
B
258
335*
0.63
A
A
259
333*
0.42
A
A
260
333*
0.40
A
A
261
360*
0.51
A
A
B
262
330*
0.46
A
A
263
366
3.75
B
A
B
264
407
5.22
B
A
B
265
384
4.25
B
A
C
266
346*
2.68
B
A
C
267
366
3.38
B
A
268
316
0.82
B
A
269
384
3.83
B
A
270
316*
0.40
A
A
271
346
2.27
B
A
272
307
0.69
A
A
273
321*
0.59
A
A
A
274
317
2.18
B
A
275
321*
0.60
A
A
B
276
317
1.47
B
A
277
407*
0.81
A
A
B
278
316
1.08
B
A
279
316*
0.45
A
A
280
329
0.78
A
A
281
329
0.78
A
A
282
199*
0.3
A
r
283
228
0.53
A
r
284
184
0.48
A
r
B
285
321**
0.87
A
r
286
338
1.03
A
r
A
287
310
0.73
A
r
B
288
256
0.74
A
r
289
212
0.66
A
r
290
338
1.01
A
r
A
291
269
0.71
A
r
292
269
0.66
A
r
293
267
0.68
A
r
294
281
0.76
A
r
295
311
0.65
A
r
296
444
0.95
A
r
297
466**
0.96
A
r
298
351
0.87
A
r
299
343
0.94
A
r
300
305
0.62
A
r
301
300
0.88
A
r
A
302
303
0.83
A
r
303
281
0.68
A
r
304
387**
1
A
r
B
305
338
0.87
A
r
B
306
266
1.00
A
r
B
307
288
0.95
A
r
A
308
268
0.69
A
r
C
309
304**
0.74
A
r
310
274
0.93
A
r
B
311
288
0.96
A
r
C
312
328
0.94
A
r
C
313
393
1.01
A
r
C
314
422
1.27
A
r
315
292
1.05
A
r
B
316
320
1.14
A
r
B
317
364
1
A
r
B
318
286
0.97
A
r
B
319
261
0.47
A
r
320
262
0.61
A
r
321
344
0.66
A
r
B
322
330
0.61
A
r
B
323
301
0.58
A
r
A
324
358
0.94
A
r
A
325
373
0.74
A
r
326
336
1.11
A
r
A
327
336
1.09
A
r
B
328
336
1.06
A
r
B
329
304
0.92
A
r
B
330
340**
0.85
A
r
B
331
318
0.79
A
r
332
332
0.84
A
r
333
352
1.08
A
r
A
334
352
1.07
A
r
335
352
1.07
A
r
B
336
375
0.86
A
r
337
391
0.78
A
r
338
470
1.23
A
r
B
339
606
1.13
A
r
B
340
310
1.03
A
r
A
341
310
1.01
A
r
B
342
314
1.10
A
r
A
343
311*
0.58
A
r
B
344
311*
0.85
A
r
A
345
298
1.00
A
r
A
346
318
0.89
A
r
B
347
331*
0.92
A
r
A
348
327
0.78
A
r
349
312
1.05
A
r
A
350
311*
0.64
A
r
A
351
311*
0.61
A
r
B
352
313
0.95
A
r
A
353
313
0.96
A
r
A
354
331
0.91
A
r
A
355
311*
0.60
A
r
B
356
311*
0.61
A
r
B
357
311*
0.65
A
r
A
358
300
0.79
A
r
359
300
0.82
A
r
360
314
0.87
A
r
A
361
439
1.05
A
r
362
377
0.99
A
r
A
363
260
0.88
A
r
A
364
310
0.72
A
A
B
365
310
0.72
A
B
366
513
1.03
A
r
B
367
328
0.99
A
r
A
368
396
1.09
A
r
A
369
325
0.88
A
r
B
370
385
0.88
A
r
371
476
0.73
A
r
372
407
0.89
A
r
373
419
0.98
A
r
C
374
454
1.16
A
r
B
375
434
1.12
A
r
B
376
394
1.13
A
r
B
377
352
1.06
A
A
A
378
352
1.07
A
B
A
379
291
0.64
A
r
380
291
0.63
A
r
381
312
1.04
A
A
A
382
311
0.85
A
A
A
383
311
0.64
A
A
A
384
298
1
A
A
A
385
252
0.76
A
r
386
261
0.56
A
r
B
387
290
0.91
A
r
A
388
290
0.89
A
r
A
389
290
0.87
A
r
A
390
350
0.84
A
r
B
391
291
0.5
A
r
392
291
0.8
A
r
A
393
291
0.83
A
r
A
394
298
0.99
A
B
B
395
329
0.81
A
r
B
396
329
0.89
A
r
B
397
322**
1.02
A
r
A
398
291
0.57
A
r
B
399
321
0.96
A
r
A
400
290
0.54
A
r
B
401
275
0.51
A
r
C
402
305
0.75
A
r
B
403
359
0.55
A
r
404
291
0.73
A
r
A
405
317
0.59
A
r
B
406
317
0.6
A
r
C
407
262*
0.68
A
r
B
408
312
0.93
A
r
A
409
261*
0.45
A
r
410
227
0.72
A
r
411
227
0.79
A
r
412
305
0.53
A
r
B
413
276
0.75
A
r
B
414
302
0.89
A
r
A
415
330
0.92
A
r
B
416
276
0.76
A
r
B
417
312
0.83
A
r
B
418
235
0.65
A
r
419
330
0.87
A
r
B
420
343
0.94
A
r
B
421
290
0.79
A
r
B
422
250
0.68
A
r
C
423
262
0.7
A
r
B
424
331
0.85
A
r
C
425
357
0.91
A
r
B
426
354
0.73
A
r
427
330
0.83
A
r
428
262
0.68
A
r
C
429
371
0.95
A
r
B
430
397
1
A
r
B
431
276
0.61
A
r
432
262
0.57
A
r
433
276
0.77
A
r
B
434
276
0.68
A
r
435
325
1
A
r
A
436
319
0.93
A
r
A
437
408
0.88
A
r
B
438
279
0.76
A
r
B
439
295
0.83
A
A
A
440
325
1.01
A
A
A
441
407
0.75
A
A
A
442
421
0.79
A
A
A
443
279
0.76
A
A
B
444
368
0.94
A
A
A
445
341
4.52
B
r
B
446
368
0.94
A
A
A
447
368
0.88
A
A
A
448
341
0.69
A
A
449
442
5.7
C
A
B
450
332
0.61
A
A
A
451
267*
0.44
A
r
452
323
0.84
A
r
B
453
437
0.84
A
A
A
454
437
0.85
A
A
A
455
386
0.85
A
r
456
392
0.92
A
r
457
338
0.72
A
r
458
371
0.85
A
r
459
374
0.62
A
A
B
460
400
5.02
B
r
461
437
0.72
A
r
B
*[M + H]+ of free form,
**[M + Na]−
Saitoh, Fumihiko, Kamino, Tomoyuki, Nakahara, Motoi
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